Psilocin derivatives as serotonergic psychedelic agents for the treatment of CNS disorders

ABSTRACT

The present application relates to psilocin derivatives of Formula (I), to processes for their preparation, to compositions comprising them and to their use in activation of a serotonin receptor in a cell, as well as to treating diseases, disorders or conditions by activation of a serotonin receptor in a cell.

RELATED APPLICATIONS

The present application is a divisional of co-pending U.S. patentapplication Ser. No. 17/387,845 filed on Jul. 28, 2021, which is acontinuation of co-pending International patent application no.PCT/CA2021/050123 filed Feb. 4, 2021 which claims the benefit ofpriority of U.S. provisional patent application No. 62/969,934 filed onFeb. 4, 2020 the contents of each of which are incorporated herein byreference in their entirety.

FIELD

The application relates to novel psilocin derivatives of Formula (I) forthe treatment of different conditions that are treated by activation ofserotonin receptor, for example, mental illnesses and other neurologicaldiseases, disorders and conditions, in the fields of psychiatry,neurobiology and pharmacotherapy. The present application furthercomprises methods for making the compounds of Formula (I) andcorresponding intermediates.

BACKGROUND OF THE APPLICATION

Mental health disorders, or mental illness, refer to a wide range ofdisorders that include, but are not limited to, depressive disorders,anxiety and panic disorders, schizophrenia, eating disorders, substancemisuse disorders, post-traumatic stress disorder, attentiondeficit/hyperactivity disorder and obsessive compulsive disorder. Theseverity of symptoms varies such that some individuals experiencedebilitating disease that precludes normal social function, while otherssuffer with intermittent repeated episodes across their lifespan.Although the presentation and diagnostic criteria among mental illnessconditions are distinct in part, there are common endophenotypes of noteacross the diseases, and often comorbidities exist. Specifically, thereexist phenotypic endophenotypes associated with alterations in mood,cognition and behavior. Interestingly, many of these endophenotypesextend to neurological conditions as well. For example, attentionaldeficits are reported in patients with attention deficit disorder,attention deficit hyperactivity disorder, eating disorders, substanceuse disorders, schizophrenia, depression, obsessive compulsive disorder,traumatic brain injury, Fragile X, Alzheimer's disease, Parkinson'sdisease and frontotemporal dementia.

Many mental health disorders, as well as neurological disorders, areimpacted by alterations, dysfunction, degeneration, and/or damage to thebrain's serotonergic system, which may explain, in part, commonendophenotypes and comorbidities among neuropsychiatric and neurologicaldiseases. Many therapeutic agents that modulate serotonergic functionare commercially available, including serotonin reuptake inhibitors,selective serotonin reuptake inhibitors, antidepressants, monoamineoxidase inhibitors, and, while primarily developed for depressivedisorders, many of these therapeutics are used across multiple medicalindications including, but not limited to, depression in Alzheimer'sdisease and other neurodegenerative disease, chronic pain, existentialpain, bipolar disorder, obsessive compulsive disorder, anxiety disordersand smoking cessation. However, in many cases, the marketed drugs showlimited benefit compared to placebo, can take six weeks to work and forsome patients, and are associated with several side effects includingtrouble sleeping, drowsiness, fatigue, weakness, changes in bloodpressure, memory problems, digestive problems, weight gain and sexualproblems.

The field of psychedelic neuroscience has witnessed a recent renaissancefollowing decades of restricted research due to their legal status.Psychedelics are one of the oldest classes of psychopharmacologicalagents known to man and cannot be fully understood without reference tovarious fields of research, including anthropology, ethnopharmacology,psychiatry, psychology, sociology, and others. Psychedelics(serotonergic hallucinogens) are powerful psychoactive substances thatalter perception and mood and affect numerous cognitive processes. Theyare generally considered physiologically safe and do not lead todependence or addiction. Their origin predates written history, and theywere employed by early cultures in many sociocultural and ritualcontexts. After the virtually contemporaneous discovery of(5R,8R)-(+)-lysergic acid-N,N-diethylamide (LSD) and the identificationof serotonin in the brain, early research focused intensively on thepossibility that LSD and other psychedelics had a serotonergic basis fortheir action. Today there is a consensus that psychedelics are agonistsor partial agonists at brain serotonin 5-hydroxytryptamine 2A (5-HT2A)receptors, with particular importance on those expressed on apicaldendrites of neocortical pyramidal cells in layer V, but also may bindwith lower affinity to other receptors such as the sigma-1 receptor.Several useful rodent models have been developed over the years to helpunravel the neurochemical correlates of serotonin 5-HT2A receptoractivation in the brain, and a variety of imaging techniques have beenemployed to identify key brain areas that are directly affected bypsychedelics.

Psychedelics have both rapid onset and persisting effects long aftertheir acute effects, which includes changes in mood and brain function.Long lasting effects may result from their unique receptor affinities,which affect neurotransmission via neuromodulatory systems that serve tomodulate brain activity, i.e., neuroplasticity, and promote cellsurvival, are neuroprotective, and modulate brain neuroimmune systems.The mechanisms which lead to these long-term neuromodulatory changes arelinked to epigenetic modifications, gene expression changes andmodulation of pre- and post-synaptic receptor densities. These,previously under-researched, psychedelic drugs may potentially providethe next-generation of neurotherapeutics, where treatment resistantpsychiatric and neurological diseases, e.g., depression, post-traumaticstress disorder, dementia and addiction, may become treatable withattenuated pharmacological risk profiles.

Although there is a general perception that psychedelic drugs aredangerous, from a physiologic safety standpoint, they are one of thesafest known classes of CNS drugs. They do not cause addiction, and nooverdose deaths have occurred after ingestion of typical doses ofclassical psychotic agents, such as LSD, psilocybin, or mescaline(Scheme 1). Preliminary data show that psychedelic administration inhumans results in a unique profile of effects and potential adversereactions that need to be appropriately addressed to maximize safety.The primary safety concerns are largely psychologic, rather thanphysiologic, in nature. Somatic effects vary but are relativelyinsignificant, even at doses that elicit powerful psychologic effects.Psilocybin, when administered in a controlled setting, has frequentlybeen reported to cause transient, delayed headache, with incidence,duration, and severity increased in a dose-related manner [Johnson etal., Drug Alcohol Depend (2012) 123(1-3):132-140]. It has been foundthat repeated administration of psychedelics leads to a very rapiddevelopment of tolerance known as tachyphylaxis, a phenomenon believedto be mediated, in part, by 5-HT2A receptors. In fact, several studieshave shown that rapid tolerance to psychedelics correlates withdownregulation of 5-HT2A receptors. For example, daily LSDadministration selectively decreased 5-HT2 receptor density in the ratbrain [Buckholtz et al., Eur. J. Pharmacol. 1990, 109:421-425. 1985;Buckholtz et al., Life Sci. 1985, 42:2439-2445].

Scheme 1: Chemical Structures of or Mescaline (i), LSD (ii), Psilocybin(iii) and Psilocin (iv)

Classic psychedelics and dissociative psychedelics are known to haverapid onset antidepressant and anti-addictive effects, unlike anycurrently available treatment. Randomized clinical control studies haveconfirmed antidepressant and anxiolytic effects of classic psychedelicsin humans. Ketamine also has well established antidepressant andanti-addictive effects in humans mainly through its action as an NMDAantagonist. Ibogaine has demonstrated potent anti-addictive potential inpre-clinical studies and is in the early stages of clinical trials todetermine efficacy in robust human studies [Barsuglia et al., Prog BrainRes, 2018, 242:121-158; Corkery, Prog Brain Res, 2018, 242:217-257].

Psilocybin (4-phosphoryloxy-N,N-dimethyltrypatmine (iii, Scheme 1) hasthe chemical formula C₁₂H₁₇N₂O₄P. It is a tryptamine and is one of themajor psychoactive constituents in mushrooms of the psilocybe species.It was first isolated from psilocybe mushrooms by Hofmann in 1957, andlater synthesized by him in 1958 [Passie et al. Addict Biol., 2002,7(4):357-364], and was used in psychiatric and psychological researchand in psychotherapy during the early to mid-1960s up until itscontrolled drug scheduling in 1970 in the US, and up until the 1980s inGermany [Passie 2005; Passie et al. Addict Biol., 2002, 7(4):357-364].Research into the effects of psilocybin resumed in the mid-1990s, and itis currently the preferred compound for use in studies of the effects ofserotonergic hallucinogens [Carter et al. J. Cogn. Neurosci., 200517(10):1497-1508; Gouzoulis-Mayfrank et al. Neuropsychopharmacology1999, 20(6):565-581; Hasler et al, Psychopharmacology (Berl) 2004,172(2):145-156], likely because it has a shorter duration of action andsuffers from less notoriety than LSD. Like other members of this class,psilocybin induces sometimes profound changes in perception, cognitionand emotion, including emotional lability.

In humans as well as other mammals, psilocybin is transformed into theactive metabolite psilocin, or 4-hydroxy-N,N-dimethyltryptamine (iv,Scheme 1). It is likely that psilocin partially or wholly produces mostof the subjective and physiological effects of psilocybin in humans andnon-human animals. Recently, human psilocybin research confirms the5HT2A activity of psilocybin and psilocin, and provides some support forindirect effects on dopamine through 5HT2A activity and possibleactivity at other serotonin receptors. In fact, the most consistentfinding for involvement of other receptors in the actions ofpsychedelics is the 5-HT1A receptor. That is particularly true fortryptamines and LSD, which generally have significant affinity andfunctional potency at this receptor. It is known that 5-HT1A receptorsare colocalized with 5-HT2A receptors on cortical pyramidal cells[Martin-Ruiz et al. J Neurosci. 2001, 21(24):9856-986], where the tworeceptor types have opposing functional effects [Araneda et al.Neuroscience 1991, 40(2):399-412].

Although the exact role of the 5-HT2A receptor, and other 5-HT2 receptorfamily members, is not well understood with respect to the amygdala, itis evident that the 5-HT2A receptor plays an important role in emotionalresponses and is an important target to be considered in the actions of5-HT2A agonist psychedelics. In fact, a majority of known 5HT2A agonistsproduce hallucinogenic effects in humans, and rodents generalize fromone 5HT2A agonist to others, as between psilocybin and LSD [Aghajanianet al., Eur J Pharmacol., 1999, 367(2-3):197-206; Nichols at al., JNeurochem., 2004, 90(3):576-584]. Psilocybin has a stronger affinity forthe human 5HT2A receptor than for the rat receptor and it has a lowerK(i) for both 5HT2A and 5HT2C receptors than LSD. Moreover, results froma series of drug-discrimination studies in rats found that 5HT2Aantagonists, and not 5HT1A antagonists, prevented rats from recognizingpsilocybin [Winter et al., Pharmacol Biochem Behav., 2007,87(4):472-480]. Daily doses of LSD and psilocybin reduce 5HT2 receptordensity in rat brain.

Clinical studies in the 1960s and 1970s showed that psilocybin producesan altered state of consciousness with subjective symptoms such as“marked alterations in perception, mood, and thought, changes inexperience of time, space, and self.” Psilocybin was used inexperimental research for the understanding of etiopathogenesis ofselective mental disorders and showed psychotherapeutic potential[Rucker et al., Psychopharmacol., 2016, 30(12):1220-1229]. Psilocybinbecame increasingly popular as a hallucinogenic recreational drug andwas eventually classed as a Schedule I controlled drug in 1970. Fear ofpsychedelic abuse led to a significant reduction in research being donein this area until the 1990s when human research of psilocybin wasrevived when conditions for safe administration were established[Johnson et al., Psychopharmacol., 2008, 22(6):603-620]. Today,psilocybin is one of the most widely used psychedelics in human studiesdue to its relative safety, moderately long active duration, and goodabsorption in subjects. There remains strong research and therapeuticpotential for psilocybin as recent studies have shown varying degrees ofsuccess in neurotic disorders, alcoholism, depression in terminally illcancer patients, obsessive compulsive disorder, addiction, anxiety,post-traumatic stress disorder and even cluster headaches. It could alsobe useful as a psychosis model for the development of new treatments forpsychotic disorders. [Dubovyk and Monahan-Vaughn, ACS Chem. Neurosci.(2018), 9(9):2241-2251].

Recent developments in the field have occurred in clinical research,where several double-blind placebo-controlled phase 2 studies ofpsilocybin-assisted psychotherapy in patients with treatment resistant,major depressive disorder and cancer-related psychosocial distress havedemonstrated unprecedented positive relief of anxiety and depression.Two recent small pilot studies of psilocybin assisted psychotherapy alsohave shown positive benefit in treating both alcohol and nicotineaddiction. Recently, blood oxygen level-dependent functional magneticresonance imaging and magnetoencephalography have been employed for invivo brain imaging in humans after administration of a psychedelic, andresults indicate that intravenously administered psilocybin and LSDproduce decreases in oscillatory power in areas of the brain's defaultmode network [Nichols D E. Pharmacol Rev., 2016, 68(2):264-355].

Preliminary studies using positron emission tomography (PET) showed thatpsilocybin ingestion (15 or 20 mg orally) increased absolute metabolicrate of glucose in frontal, and to a lesser extent in other, corticalregions as well as in striatal and limbic subcortical structures inhealthy participants, suggesting that some of the key behavioral effectsof psilocybin involve the frontal cortex [Gouzoulis-Mayfrank et al.,Neuropsychopharmacology, 1999, 20(6):565-581; Vollenweider et al., BrainRes. Bull. 2001, 56(5):495-507]. Although 5HT2A agonism is widelyrecognized as the primary action of classic psychedelic agents,psilocybin has lesser affinity for a wide range of other pre- andpost-synaptic serotonin and dopamine receptors, as well as the serotoninreuptake transporter [Tyls et al., Eur. Neuropsychopharmacol., 2014,24(3):342-356]. Psilocybin activates 5HT1A receptors, which maycontribute to antidepressant/anti-anxiety effects.

Depression and anxiety are two of the most common psychiatric disordersworldwide. Depression is a multifaceted condition characterized byepisodes of mood disturbances alongside other symptoms such asanhedonia, psychomotor complaints, feelings of guilt, attentionaldeficits and suicidal tendencies, all of which can range in severity.According to the World Health Organization, the discovery of mainstreamantidepressants has largely revolutionized the management of depression,yet up to 60% of patients remain inadequately treated. This is often dueto the drugs' delayed therapeutic effect (generally 6 weeks fromtreatment onset), side effects leading to non-compliance, or inherentnon-responsiveness to them. Similarly, anxiety disorders are acollective of etiologically complex disorders characterized by intensepsychosocial distress and other symptoms depending on the subtype.Anxiety associated with life-threatening disease is the only anxietysubtype that has been studied in terms of psychedelic-assisted therapy.This form of anxiety affects up to 40% of individuals diagnosed withlife-threatening diseases like cancer. It manifests as apprehensionregarding future danger or misfortune accompanied by feelings ofdysphoria or somatic symptoms of tension, and often coexists withdepression. It is associated with decreased quality of life, reducedtreatment adherence, prolonged hospitalization, increased disability,and hopelessness, which overall contribute to decreased survival rates.Pharmacological and psychosocial interventions are commonly used tomanage this type of anxiety, but their efficacy is mixed and limitedsuch that they often fail to provide satisfactory emotional relief.Recent interest into the use of psychedelic-assisted therapy mayrepresent a promising alternative for patients with depression andanxiety that are ineffectively managed by conventional methods.

Generally, the psychedelic treatment model consists of administering theorally-active drug to induce a mystical experience lasting 4-9 hdepending on the psychedelic [Halberstadt, Behav Brain Res., 2015,277:99-120; Nichols, Pharmacol Rev., 2016, 68(2): 264-355]. This enablesparticipants to work through and integrate difficult feelings andsituations, leading to enduring anti-depressant and anxiolytic effects.Classical psychedelics like psilocybin and LSD are being studied aspotential candidates. In one study with classical psychedelics for thetreatment of depression and anxiety associated with life-threateningdisease, it was found that, in a supportive setting, psilocybin, and LSDconsistently produced significant and sustained anti-depressant andanxiolytic effects.

Psychedelic treatment is generally well-tolerated with no persistingadverse effects. Regarding their mechanisms of action, they mediatetheir main therapeutic effects biochemically via serotonin receptoragonism, and psychologically by generating meaningful psycho-spiritualexperiences that contribute to mental flexibility. Given the limitedsuccess rates of current treatments for anxiety and mood disorders, andconsidering the high morbidity associated with these conditions, thereis potential for psychedelics to provide symptom relief in patientsinadequately managed by conventional methods.

Further emerging clinical research and evidence suggestpsychedelic-assisted therapy, also shows potential as an alternativetreatment for refractory substance use disorders and mental healthconditions, and thus may be an important tool in a crisis where existingapproaches have yielded limited success. A recent systematic review ofclinical trials published over the last 25 years summarizes some of theanti-depressive, anxiolytic, and anti-addictive effects of classicpsychedelics. Among these, are encouraging findings from a meta-analysisof randomized controlled trials of LSD therapy and a recent pilot studyof psilocybin-assisted therapy for treating alcohol use disorder [dosSantos et al., Ther Adv Psychopharmacol., 2016, 6(3):193-213]. Similarlyencouraging, are findings from a recent pilot study ofpsilocybin-assisted therapy for tobacco use disorder, demonstratingabstinence rates of 80% at six months follow-up and 67% at 12 monthsfollow-up [Johnson et al., J Drug Alcohol Abuse, 2017, 43(1):55-60;Johnson et al., Psychopharmacol. 2014, 28(11):983-992], such rates areconsiderably higher than any documented in the tobacco cessationliterature. Notably, mystical-type experiences generated from thepsilocybin sessions were significantly correlated with positivetreatment outcomes. These results coincide with bourgeoning evidencefrom recent clinical trials lending support to the effectiveness ofpsilocybin-assisted therapy for treatment-resistant depression andend-of-life anxiety [Carhart-Harris et al. Neuropsychopharmacology,2017, 42(11):2105-2113]. Research on the potential benefits ofpsychedelic-assisted therapy for opioid use disorder (OUD) is beginningto emerge, and accumulating evidence supports a need to advance thisline of investigation. Available evidence from earlier randomizedclinical trials suggests a promising role for treating OUD: higher ratesof abstinence were observed among participants receiving high dose LSDand ketamine-assisted therapies for heroin addiction compared tocontrols at long-term follow-ups. Recently, a large United Statespopulation study among 44,000 individuals found that psychedelic use wasassociated with 40% reduced risk of opioid abuse and 27% reduced risk ofopioid dependence in the following year, as defined by DSM-IV criteria[Pisano et al., J Psychopharmacol., 2017, 31(5):606-613]. Similarly, aprotective moderating effect of psychedelic use was found on therelationship between prescription opioid use and suicide risk amongmarginalized women [Argento et al., J Psychopharmacol., 2018,32(12):1385-1391]. Despite the promise of these preliminary findingswith classical psychedelic agents, further research is warranted todetermine what it may contribute to the opioid crisis response giventheir potential toxicity. Meanwhile, growing evidence on the safety andefficacy of psilocybin for the treatment of mental and substance usedisorders should help to motivate further clinical investigation intoits use as a novel intervention for OUD.

Regular doses of psychedelics also ameliorate sleep disturbances, whichare highly prevalent in depressive patients with more than 80% of themhaving complaints of poor sleep quality. The sleep symptoms are oftenunresolved by first-line treatment and are associated with a greaterrisk of relapse and recurrence. Interestingly, sleep problems oftenappear before other depression symptoms, and subjective sleep qualityworsens before the onset of an episode in recurrent depression. Brainareas showing increased functional connectivity with poor sleep scoresand higher depressive symptomatology scores included prefrontal andlimbic areas, areas involved in the processing of emotions. Sleepdisruption in healthy participants has demonstrated that sleep is indeedinvolved in mood, emotion evaluation processes and brain reactivity toemotional stimuli. An increase in negative mood and a mood-independentmislabeling of neutral stimuli as negative was for example shown by onestudy while another demonstrated an amplified reactivity in limbic brainregions in response to both negative and positive stimuli. Two otherstudies assessing electroencephalographic (EEG) brain activity duringsleep showed that psychedelics, such as LSD, positively affect sleeppatterns. Moreover, it has been shown that partial or a full night ofsleep deprivation can alleviate symptoms of depression suggested byresetting circadian rhythms via modification of clock gene expression.It further was suggested that a single dose of a psychedelic causes areset of the biological clock underlying sleep/wake cycles and therebyenhances cognitive-emotional processes in depressed people but alsoimproving feelings of well-being and enhances mood in healthyindividuals [Kuypers, Medical Hypotheses, 2019, 125:21-24].

In a systematic meta-analysis of clinical trials from 1960-2018researching the therapeutic use of psychedelic treatment in patientswith serious or terminal illnesses and related psychiatric illness, itwas found that psychedelic therapy (mostly with LSD) may improvecancer-related depression, anxiety, and fear of death. Four randomizedcontrolled clinical trials were published between 2011 and 2016, mostlywith psilocybin treatment, that demonstrated psychedelic-assistedtreatment can produce rapid, robust, and sustained improvements incancer-related psychological and existential distress. [Ross S, Int RevPsychiatry, 2018, 30(4):317-330]. Thus, the use of psychedelics in thefields of oncology and palliative care is intriguing for severalreasons. First, many patients facing cancer or other life-threateningillnesses experience significant existential distress related to loss ofmeaning or purpose in life, which can be associated with hopelessness,demoralization, powerlessness, perceived burdensomeness, and a desirefor hastened death. Those features are also often at the core ofclinically significant anxiety and depression, and they cansubstantially diminish quality of life in this patient population. Thealleviation of those forms of suffering should be among the central aimsof palliative care. Accordingly, several manualized psychotherapies forcancer-related existential distress have been developed in recent years,with an emphasis on dignity and meaning-making. However, there arecurrently no pharmacologic interventions for existential distress perse, and available pharmacologic treatments for depressive symptoms inpatients with cancer have not demonstrated superiority over placebo.There remains a need for additional effective treatments for thoseconditions [Rosenbaum et al., Curr. Oncol., 2019, 26(4): 225-226].

Recently, there has been growing interest in a new dosing paradigm forpsychedelics such as psilocybin and LSD referred to colloquially asmicrodosing. Under this paradigm, sub-perceptive doses of theserotonergic hallucinogens, approximately 10% or less of the full dose,are taken on a more consistent basis of once each day, every other day,or every three days, and so on. Not only is this dosing paradigm moreconsistent with current standards in pharmacological care, but may beparticularly beneficial for certain conditions, such as Alzheimer'sdisease and other neurodegenerative diseases, attention deficitdisorder, attention deficit hyperactivity disorder, and for certainpatient populations such as elderly, juvenile and patients that arefearful of or opposed to psychedelic assisted therapy. Moreover, thisapproach may be particularly well suited for managing cognitive deficitsand preventing neurodegeneration. For example, subpopulations of lowattentive and low motivated rats demonstrate improved performance on 5choice serial reaction time and progressive ratio tasks, respectively,following doses of psilocybin below the threshold for eliciting theclassical wet dog shake behavioral response associated withhallucinogenic doses (Blumstock et al., WO 2020/157569 A1). Similarly,treatment of patients with hallucinogenic doses of 5HT2A agonists isassociated with increased BDNF and activation of the mTOR pathway, whichare thought to promote neuroplasticity and are hypothesized to serve asmolecular targets for the treatment of dementias and otherneurodegenerative disorders (Ly et al. Cell Rep., 2018,23(11):3170-3182). Additionally, several groups have demonstrated thatlow, non-hallucinogenic and non-psychomimetic, doses of 5HT2A agonistsalso show similar neuroprotective and increased neuroplasticity effects(neuroplastogens) and reduced neuroinflammation, which could bebeneficial in both neurodegenerative and neurodevelopmental diseases andchronic disorders (Manfredi et al., WO 2020/181194, Flanagan et al.,Int. Rev. Psychiatry, 2018, 13:1-13; Nichols et al., 2016, Psychedelicsas medicines; an emerging new paradigm). This repeated, lower, doseparadigm may extend the utility of these compounds to additionalindications and may prove useful for wellness applications.

Psychosis is often referred to as an abnormal state of mind that ischaracterized by hallucinatory experiences, delusional thinking, anddisordered thoughts. Moreover, this state is accompanied by impairmentsin social cognition, inappropriate emotional expressions, and bizarrebehavior. Most often, psychosis develops as part of a psychiatricdisorder, of which, it represents an integral part of schizophrenia. Itcorresponds to the most florid phase of the illness. The very firstmanifestation of psychosis in a patient is referred to as first-episodepsychosis. It reflects a critical transitional stage toward the chronicestablishment of the disease, that is presumably mediated by progressivestructural and functional abnormalities seen in diagnosed patients. [ACSChem. Neurosci., 2018, 9, 2241-2251]. Anecdotal evidence suggests thatlow, non-hallucinogenic, doses (microdosing) of psychedelics that areadministered regularly can reduce symptoms of schizophrenia andpsychosis.

SUMMARY OF THE APPLICATION

The present application includes a compound of Formula (I) or apharmaceutically acceptable salt, solvate and/or prodrug thereof:

wherein R¹ is selected from hydrogen, C₁-C₃ alkyl, C(O)R¹², CO₂OR¹²,C(O)N(R¹²)₂, S(O)R¹² and SO₂R¹²;R³, R⁴, R⁵ and R⁶ are independently selected from hydrogen andC₁-C₆alkyl;R⁷ and R³ are independently selected from hydrogen, substituted orunsubstituted C₁-C₆alkyl, substituted or unsubstituted C₂-C₆alkenyl,substituted or unsubstituted C₂-C₆alkynyl, substituted or unsubstitutedC₁-C₆haloalkyl, substituted or unsubstituted C₃-C₇cycloalkyl,substituted or unsubstituted C₃-C₇heterocycloalkyl, substituted orunsubstituted aryl and substituted or unsubstituted heteroaryl, orR⁷ and R⁸ are taken together with the nitrogen atom therebetween to forma 3- to 7-membered heterocyclic ring optionally including 1 to 2additional ring heteromoieties selected from O, S, S(O), SO₂, N andNR¹³,wherein said C₃-C₇cycloalkyl and 3- to 7-membered heterocyclic ring areeach further optionally substituted with a substituent selected fromhalogen, CO₂R¹³, C(O)N(R¹³)₂, SO₂R¹³, C₁-C₆alkyl, C₁-C₆haloalkyl,C₂-C₆alkenyl, C₂-C₆haloalkenyl, C₂-C₆alkynyl, C₂-C₆haloalkynyl,C₃-C₆cycloalkyl and a 3- to 6-membered heterocyclic ring including 1 to2 ring heteromoieties selected from O, S, N, S(O), SO₂ and NR¹³;R⁹, R¹⁰ and R¹¹ are independently selected from hydrogen, halogen, CN,OR¹³, N(R¹³)₂, SR¹³, C₁-C₆alkyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl,CO₂R¹³, C(O)N(R¹³)₂, SOR¹³, SO₂R¹³, C₂-C₆alkenyl, C₂-C₆alkynyl,C₂-C₆haloalkynyl, C₃-C₆cycloalkyl and a 3- to 7-membered heterocyclicring including 1 to 2 ring heteromoieties selected from O, S, S(O), SO₂,N and NR¹³, wherein said C₁-C₆alkyl, C₁-C₆haloalkyl, C₂-C₆alkenyl,C₂-C₆haloalkenyl, C₂-C₆alkynyl, C₂-C₆haloalkynyl, C₃-C₆cycloalkyl and 3-to 7-membered heterocyclic ring groups are optionally substituted by oneor more substituents independently selected from CN, OR¹³, N(R¹³)₂ andSR¹³, and wherein said C₃-C₆cycloalkyl and 3- to 7-membered heterocyclicring are each further optionally substituted with a substituent selectedfrom halogen, CO₂R¹³, C(O)N(R¹³)₂, SO₂R¹³, C₁-C₆alkyl, C₁-C₆haloalkyl,C₂-C₆alkenyl, C₂-C₆haloalkenyl, C₂-C₆alkynyl, C₂-C₆haloalkynyl,C₃-C₆cycloalkyl and a 3- to 6-membered heterocyclic ring including 1 to2 ring heteromoieties selected from O, S, S(O), SO₂, N and NR¹³;Y is selected from halogen and X-A;X is selected from O, NR¹³, S, S(O) and SO₂;A is selected from hydrogen, C₁-C₁₀alkyl, C₂-C₁₀alkenyl, C₂-C₁₀alkynyl,C₃-C₆cycloalkyl, C₄-C₆cycloalkenyl, heterocycloalkyl, aryl, heteroaryl,and P(O)(OR¹²)₂;each R¹² is independently selected from hydrogen, substituted orunsubstituted C₁-C₆alkyl, substituted or unsubstituted C₂-C₆alkenyl,substituted or unsubstituted C₂-C₆alkynyl, substituted or unsubstitutedC₁-C₆haloalkyl, substituted or unsubstituted C₃-C₇cycloalkyl,substituted or unsubstituted C₃-C₇heterocycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted C₁-C₆alkyleneC₃-C₇cycloalkyl, substituted orunsubstituted C₁-C₆alkyleneC₃-C₇heterocycloalkyl, substituted orunsubstituted C₁-C₆alkylenearyl, and substituted or unsubstitutedC₁-C₆alkyleneheteroaryl;each R¹³ is independently selected from hydrogen, C₁-C₆alkyl,C₁-C₆haloalkyl, C₂-C₆alkenyl, C₂-C₆haloalkenyl, C₂-C₆alkynyl,C₂-C₆haloalkynyl, C₃-C₆cycloalkyl, and a 3- to 7-membered heterocyclicring including 1 to 2 ring heteromoieties selected from O, S, S(O), SO₂,N and NR¹⁴, wherein said C₁-C₆alkyl, C₁-C₆haloalkyl, C₂-C₆alkenyl,C₂-C₆haloalkenyl, C₂-C₆alkynyl, C₂-C₆haloalkynyl, C₃-C₇cycloalkyl and 3-to 7-membered heterocyclic ring groups are optionally substituted by oneor more substituents independently selected from CN, OR¹⁴, N(R¹⁴)₂ andSR¹⁴, and wherein said C₃-C₇cycloalkyl and 3- to 7-membered heterocyclicring are each further optionally substituted with a substituent selectedfrom halogen, CO₂R¹⁴, C(O)N(R¹⁴)₂, SO₂R¹⁴, C₁-C₆alkyl, C₁-C₆haloalkyl,C₂-C₆alkenyl, C₂-C₆haloalkenyl, C₂-C₆alkynyl, C₂-C₆haloalkynyl,C₃-C₆cycloalkyl and a 3- to 6-membered heterocyclic ring including 1 to2 ring heteromoieties selected from O, S, S(O), SO₂, N and NR¹⁴,R¹⁴ is selected from hydrogen, substituted or unsubstituted C₁-C₆alkyl,substituted or unsubstituted C₂-C₆alkenyl, substituted or unsubstitutedC₂-C₆alkynyl, substituted or unsubstituted C₁-C₆haloalkyl, substitutedor unsubstituted C₃-C₇cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl and substituted orunsubstituted heteroaryl;wherein at least one of R³, R⁴, R⁵ and R⁶ is deuterium or at least oneof R³, R⁴, R⁵ and R⁶ comprises deuterium, andwherein all available hydrogen atoms are optionally substituted with ahalogen atom and/or all available atoms are optionally substituted withan alternate isotope thereof.

In some embodiments, the compounds of Formula (I) and pharmaceuticallyacceptable salts, solvates and/or prodrugs thereof, are isotopicallyenriched with deuterium. In some embodiments, one or more of A, X, R¹,R², R³, R⁴, R⁵, R⁶, R⁷ R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ comprises oneor more deuterium or one or more of A, X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷ R⁸,R⁹, R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ is deuterium.

In a further embodiment, the compounds of the application are used asmedicaments. Accordingly, the application also includes a compound ofthe application for use as a medicament.

The present application includes a method for activating a serotoninreceptor in a cell, either in a biological sample or in a patient,comprising administering an effective amount of one or more compounds ofthe application to the cell.

The present application also includes a method of treating psychosis orpsychotic symptoms comprising administering a therapeutically effectiveamount of one or more compounds of the application to a subject in needthereof.

The present application also includes a method of treating a mentalillness comprising administering a therapeutically effective amount ofone or more compounds of the application to a subject in need thereof.

The present application also includes a method of treating a CNSdisease, disorder or condition and/or a neurological disease, disorderor condition comprising administering a therapeutically effective amountof one or more compounds of the application to a subject in needthereof.

The application additionally provides a process for the preparation ofcompounds of the application. General and specific processes arediscussed in more detail below and set forth in the examples below.

Other features and advantages of the present application will becomeapparent from the following detailed description. It should beunderstood, however, that the detailed description and the specificexamples, while indicating embodiments of the application, are given byway of illustration only and the scope of the claims should not belimited by these embodiments, but should be given the broadestinterpretation consistent with the description as a whole.

DRAWINGS

The embodiments of the application will now be described in greaterdetail with reference to the attached drawings in which:

FIG. 1 . is a graph showing the effect of various doses of exemplarycompound of Formula I, I-45, on head-twitch response (HTR) in maleC57BL6 mice. The mice were treated with compound I-45 (0.03-10 mg/kg,SC) by SC route (N=6 mice/dose), and the total number of head twitcheswere recorded over a 1 h period. Data is expressed as mean+SEM. Theinduction of head twitches elicited by 5-HT2A receptor agonists isbelieved to represent a behavioural proxy of their psychedelic effects.

DETAILED DESCRIPTION I. Definitions

Unless otherwise indicated, the definitions and embodiments described inthis and other sections are intended to be applicable to all embodimentsand aspects of the present application herein described for which theyare suitable as would be understood by a person skilled in the art.

The term “compound(s) of the application” or “compound(s) of the presentapplication” and the like as used herein refers to a compound of Formula(I) and compounds of Formula (I-A) to (I-I) and pharmaceuticallyacceptable salts, solvates and/or prodrugs thereof.

The term “composition(s) of the application” or “composition(s) of thepresent application” and the like as used herein refers to acomposition, such a pharmaceutical composition, comprising one or morecompounds of the application.

The term “and/or” as used herein means that the listed items arepresent, or used, individually or in combination. In effect, this termmeans that “at least one of or “one or more” of the listed items is usedor present. The term “and/or” with respect to pharmaceuticallyacceptable salts, solvates and/or prodrugs thereof means that thecompounds of the application exist as individual salts, solvates andprodrugs, as well as a combination of, for example, a salt of a solvateof a compound of the application.

As used in the present application, the singular forms “a”, “an” and“the” include plural references unless the content clearly dictatesotherwise. For example, an embodiment including “a compound” should beunderstood to present certain aspects with one compound, or two or moreadditional compounds.

As used in this application and claim(s), the words “comprising” (andany form of comprising, such as “comprise” and “comprises”), “having”(and any form of having, such as “have” and “has”), “including” (and anyform of including, such as “include” and “includes”) or “containing”(and any form of containing, such as “contain” and “contains”), areinclusive or open-ended and do not exclude additional, unrecitedelements or process steps.

The term “consisting” and its derivatives as used herein are intended tobe closed terms that specify the presence of the stated features,elements, components, groups, integers and/or steps and also exclude thepresence of other unstated features, elements, components, groups,integers and/or steps.

The term “consisting essentially of”, as used herein, is intended tospecify the presence of the stated features, elements, components,groups, integers and/or steps as well as those that do not materiallyaffect the basic and novel characteristic(s) of these features,elements, components, groups, integers and/or steps.

In embodiments comprising an “additional” or “second” component, such asan additional or second compound, the second component as used herein ischemically different from the other components or first component. A“third” component is different from the other, first and secondcomponents and further enumerated or “additional” components aresimilarly different.

The term “suitable” as used herein means that the selection of theparticular compound or conditions would depend on the specific syntheticmanipulation to be performed, the identity of the molecule(s) to betransformed and/or the specific use for the compound, but the selectionwould be well within the skill of a person trained in the art. Allprocess/method steps described herein are to be conducted underconditions sufficient to provide the product shown. A person skilled inthe art would understand that all reaction conditions, including, forexample, reaction solvent, reaction time, reaction temperature, reactionpressure, reactant ratio and whether or not the reaction should beperformed under an anhydrous or inert atmosphere, can be varied tooptimize the yield of the desired product and it is within their skillto do so.

The terms “about”, “substantially” and “approximately” as used hereinmean a reasonable amount of deviation of the modified term such that theend result is not significantly changed. These terms of degree should beconstrued as including a deviation of at least ±5% of the modified termif this deviation would not negate the meaning of the word it modifiesor unless the context suggests otherwise to a person skilled in the art.

The present description refers to a number of chemical terms andabbreviations used by those skilled in the art. Nevertheless,definitions of selected terms are provided for clarity and consistency.

The term “solvate” as used herein means a compound, or a salt or prodrugof a compound, wherein molecules of a suitable solvent are incorporatedin the crystal lattice. A suitable solvent is physiologically tolerableat the dosage administered.

The term “prodrug” as used herein means a compound, or salt of acompound, that, after administration, is converted into an active drug.

The term “alkyl” as used herein, whether it is used alone or as part ofanother group, means straight or branched chain, saturated alkyl groups.The number of carbon atoms that are possible in the referenced alkylgroup are indicated by the prefix “C_(n1-n2)”. Thus, for example, theterm “C₁₋₆alkyl” (or “C₁-C₆alkyl”) means an alkyl group having 1, 2, 3,4, 5, or c carbon atoms and includes, for example, any of the hexylalkyl and pentyl alkyl isomers as well as n-, iso-, sec- and ter-butyl,n- and iso-propyl, ethyl and methyl. As another example, “C₄alkyl”refers to n-, iso-, sec- and tert-butyl, n- and isopropyl, ethyl andmethyl.

The term “alkenyl” whether it is used alone or as part of another group,means a straight or branched chain, saturated alkylene group, that is, asaturated carbon chain that contains substituents on two of its ends.The number of carbon atoms that are possible in the referenced alkylenegroup are indicated by the prefix “C_(n1-n2)”. For example, the termC₂₋₆alkylene means an alkylene group having 2, 3, 4, 5 or 6 carbonatoms.

The term “alkynyl” as used herein, whether it is used alone or as partof another group, means straight or branched chain, unsaturated alkynylgroups containing at least one triple bond. The number of carbon atomsthat are possible in the referenced alkyl group are indicated by theprefix “C_(n1-n2)”. For example, the term C₂₋₆alkynyl means an alkynylgroup having 2, 3, 4, 5 or 6 carbon atoms.

The term “cycloalkyl,” as used herein, whether it is used alone or aspart of another group, means a saturated carbocyclic group containingfrom 3 to 20 carbon atoms and one or more rings. The number of carbonatoms that are possible in the referenced cycloalkyl group are indicatedby the numerical prefix “C_(n1-n2)”. For example, the termC₃₋₁₀cycloalkyl means a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9 or10 carbon atoms.

The term “aryl” as used herein, whether it is used alone or as part ofanother group, refers to carbocyclic groups containing at least onearomatic ring and contains either 6 to 20 carbon atoms.

The term “available”, as in “available hydrogen atoms” or “availableatoms” refers to atoms that would be known to a person skilled in theart to be capable of replacement by a substituent.

The term “heterocycloalkyl” as used herein, whether it is used alone oras part of another group, refers to cyclic groups containing at leastone non-aromatic ring containing from 3 to 20 atoms in which one or moreof the atoms are a heteromoiety selected from O, S, S(O), SO₂ and N andthe remaining atoms are C. Heterocycloalkyl groups are either saturatedor unsaturated (i.e. contain one or more double bonds). When aheterocycloalkyl group contains the prefix C_(n1-n2) or “n1 to n2” thisprefix indicates the number of carbon atoms in the correspondingcarbocyclic group, in which one or more, suitably 1 to 5, of the ringatoms is replaced with a heteromoeity as selected from O, S, S(O), SO₂and N and the remaining atoms are C. Heterocycloalkyl groups areoptionally benzofused.

The term “heteroaryl” as used herein, whether it is used alone or aspart of another group, refers to cyclic groups containing at least oneheteroaromatic ring containing 5-20 atoms in which one or more of theatoms are a heteroatom selected from O, S and N and the remaining atomsare C. When a heteroaryl group contains the prefix C_(n1-n2) this prefixindicates the number of carbon atoms in the corresponding carbocyclicgroup, in which one or more, suitably 1 to 5, of the ring atoms isreplaced with a heteroatom as defined above. Heteroaryl groups areoptionally benzofused.

All cyclic groups, including aryl, heteroaryl, heterocycloalkyl andcycloalkyl groups, contain one or more than one ring (i.e. arepolycyclic). When a cyclic group contains more than one ring, the ringsmay be fused, bridged, spirofused or linked by a bond.

The term “benzofused” as used herein refers to a polycyclic group inwhich a benzene ring is fused with another ring.

A first ring being “fused” with a second ring means the first ring andthe second ring share two adjacent atoms there between.

A first ring being “bridged” with a second ring means the first ring andthe second ring share two non-adjacent atoms there between.

A first ring being “spirofused” with a second ring means the first ringand the second ring share one atom there between.

The term “halogen” (or “halo”) whether it is used alone or as part ofanother group, refers to a halogen atom and includes fluoro, chloro,bromo and iodo.

The term “haloalkyl” as used herein refers to an alkyl group as definedabove in which one or more of the available hydrogen atoms have beenreplaced with a halogen. Thus, for example, “C₁₋₆haloalkyl” (or“C₁-C₆haloalkyl”) refers to a C₁ to C₆ linear or branched alkyl group asdefined above with one or more halogen substituents.

As used herein, the term “haloalkenyl” refers to an alkenyl group asdefined above in which one or more of the available hydrogen atoms havebeen replaced with a halogen. Thus, for example, “C₁₋₆haloalkenyl” (or“C₁-C₆haloalkenyl”) refers to a C₁ to C₆ linear or branched alkenylgroup as defined above with one or more halogen substituents.

As used herein, the term “haloalkynyl” refers to an alkynyl group asdefined above in which one or more of the available hydrogen atoms havebeen replaced with a halogen. Thus, for example, “C₁₋₆haloalkynyl” (or“C₁-C₆haloalkynyl”) refers to a C₁ to C₆ linear or branched alkynylgroup as defined above with one or more halogen substituents.

As used herein, the term “alkoxy” as used herein, alone or incombination, includes an alkyl group connected to an oxygen connectingatom.

As used herein, the term “one or more” item includes a single itemselected from the list as well as mixtures of two or more items selectedfrom the list.

The term “substituted” as used herein means, unless otherwise indicated,that the referenced group is substituted with one or more substituentsindependently selected from halogen, CO₂H, CO₂CH₃, C(O)NH₂, C(O)N(CH₃)₂,C(O)NHCH₃, SO₂CH₃, SOCH₃, C₁-C₆alkyl, C₁-C₆haloalkyl, C₂-C₆alkenyl,C₂-C₆haloalkenyl, C₂-C₆alkynyl, C₂-C₆haloalkynyl, C₃-C₆cycloalkyl and a3- to 6-membered heterocyclic ring including 1 to 2 ring heteromoietiesselected from O, S, S(O), SO₂, N, NH and NCH₃.

The term “alternate isotope thereof” as used herein refers to an isotopeof an element that is other than the isotope that is most abundant innature.

In the compounds of general Formula (I) and pharmaceutically acceptablesalts, solvates and/or prodrug thereof, the atoms may exhibit theirnatural isotopic abundances, or one or more of the atoms may beartificially enriched in a particular isotope having the same atomicnumber, but an atomic mass or mass number different from the atomic massor mass number predominantly found in nature. The present disclosure ismeant to include all suitable isotopic variations of the compounds ofgeneral Formula (I) and pharmaceutically acceptable salts, solvatesand/or prodrug thereof. For example, different isotopic forms ofhydrogen (H) include protium (1H), deuterium (2H) and tritium (3H).Protium is the predominant hydrogen isotope found in nature.

The term “all available atoms are optionally substituted with alternateisotope” as used herein means that available atoms are optionallysubstituted with an isotope of that atom of having the same atomicnumber, but an atomic mass or mass number different from the atomic massor mass number predominantly found in nature.

The term “compound” refers to the compound and, in certain embodiments,to the extent they are stable, any hydrate or solvate thereof. A hydrateis the compound complexed with water and a solvate is the compoundcomplexed with a solvent, which may be an organic solvent or aninorganic solvent. A “stable” compound is a compound that can beprepared and isolated and whose structure and properties remain or canbe caused to remain essentially unchanged for a period of timesufficient to allow use of the compound for the purposes describedherein (e.g., therapeutic administration to a subject). The compounds ofthe present application are limited to stable compounds embraced bygeneral Formula (I), or pharmaceutically acceptable salts, solvatesand/or prodrug thereof.

The term “pharmaceutically acceptable” means compatible with thetreatment of subjects.

The term “pharmaceutically acceptable carrier” means a non-toxicsolvent, dispersant, excipient, adjuvant or other material which ismixed with the active ingredient in order to permit the formation of apharmaceutical composition, i.e., a dosage form capable ofadministration to a subject.

The term “pharmaceutically acceptable salt” means either an acidaddition salt or a base addition salt which is suitable for, orcompatible with, the treatment of subjects.

An acid addition salt suitable for, or compatible with, the treatment ofsubjects is any non-toxic organic or inorganic acid addition salt of anybasic compound.

A base addition salt suitable for, or compatible with, the treatment ofsubjects is any non-toxic organic or inorganic base addition salt of anyacidic compound The term “protecting group” or “PG” and the like as usedherein refers to a chemical moiety which protects or masks a reactiveportion of a molecule to prevent side reactions in those reactiveportions of the molecule, while manipulating or reacting a differentportion of the molecule. After the manipulation or reaction is complete,the protecting group is removed under conditions that do not degrade ordecompose the remaining portions of the molecule. The selection of asuitable protecting group can be made by a person skilled in the art.Many conventional protecting groups are known in the art, for example asdescribed in “Protective Groups in Organic Chemistry” McOmie, J. F. W.Ed., Plenum Press, 1973, in Greene, T. W. and Wuts, P. G. M.,“Protective Groups in Organic Synthesis”, John Wiley & Sons, 3^(rd)Edition, 1999 and in Kocienski, P. Protecting Groups, 3rd Edition, 2003,Georg Thieme Verlag (The Americas).

The term “subject” as used herein includes all members of the animalkingdom including mammals, and suitably refers to humans. Thus themethods of the present application are applicable to both human therapyand veterinary applications.

The term “treating” or “treatment” as used herein and as is wellunderstood in the art, means an approach for obtaining beneficial ordesired results, including clinical results. Beneficial or desiredclinical results include, but are not limited to alleviation oramelioration of one or more symptoms or conditions, diminishment ofextent of disease, stabilized (i.e. not worsening) state of disease,preventing spread of disease, delay or slowing of disease progression,amelioration or palliation of the disease state, diminishment of thereoccurrence of disease and remission (whether partial or total),whether detectable or undetectable. “Treating” and “treatment” can alsomean prolonging survival as compared to expected survival if notreceiving treatment. “Treating” and “treatment” as used herein alsoinclude prophylactic treatment. For example, a subject with early cancercan be treated to prevent progression, or alternatively a subject inremission can be treated with a compound or composition of theapplication to prevent recurrence. Treatment methods compriseadministering to a subject a therapeutically effective amount of one ormore of the compounds of the application and optionally consist of asingle administration, or alliteratively comprise a series ofadministrations.

As used herein, the term “effective amount” or “therapeuticallyeffective amount” means an amount of one or more compounds of theapplication that is effective, at dosages and for periods of timenecessary to achieve the desired result. For example, in the context oftreating a disease, disorder or condition mediated or treated by agonismor activation of serotonergic receptors and downstream secondmessengers, an effective amount is an amount that, for example,increases said activation compared to the activation withoutadministration of the one or more compounds.

“Palliating” a disease, disorder or condition means that the extentand/or undesirable clinical manifestations of a disease, disorder orcondition are lessened and/or time course of the progression is slowedor lengthened, as compared to not treating the disorder.

The term “administered” as used herein means administration of atherapeutically effective amount of one or more compounds orcompositions of the application to a cell, tissue, organ or subject.

The term “prevention” or “prophylaxis”, or synonym thereto, as usedherein refers to a reduction in the risk or probability of a patientbecoming afflicted with a disease, disorder or condition or manifestinga symptom associated with a disease, disorder or condition.

The “disease, disorder or condition” as used herein refers to a disease,disorder or condition treated or treatable by activation a serotoninreceptor, for example 5-HT_(2A) and particularly using a serotoninreceptor agonist, such as one or more compounds of the applicationherein described.

The term “treating a disease, disorder or condition by activation of aserotonin receptor” as used herein means that the disease, disorder orcondition to be treated is affected by, modulated by and/or has somebiological basis, either direct or indirect, that includes serotonergicactivity, in particular increases in serotonergic activity. Thesediseases respond favourably when serotonergic activity associated withthe disease, disorder or condition is agonized by one or more of thecompounds or compositions of the application.

The term “activation” as used herein includes agonism, partial agonistand positive allosteric modulation of a serotonin receptor.

The term “5-HT_(2A)” as used herein mean the 5-HT_(2A) receptor subtypeof the 5-HT₂ serotonin receptor.

The term “therapeutic agent” as used herein refers to any drug or activeagent that has a pharmacological effect when administered to a subject.

II. Compounds

The present application includes a compound of Formula (I) or apharmaceutically acceptable salt, solvate and/or prodrug thereof:

wherein R¹ is selected from hydrogen, C₁-C₃ alkyl, C(O)R¹², CO₂OR¹²,C(O)N(R¹²)₂, S(O)R¹² and SO₂R¹²;R³, R⁴, R⁵ and R⁶ are independently selected from hydrogen andC₁-C₆alkyl;R⁷ and R³ are independently selected from hydrogen, substituted orunsubstituted C₁-C₆alkyl, substituted or unsubstituted C₂-C₆alkenyl,substituted or unsubstituted C₂-C₆alkynyl, substituted or unsubstitutedC₁-C₆haloalkyl, substituted or unsubstituted C₃-C₇cycloalkyl,substituted or unsubstituted C₃-C₇heterocycloalkyl, substituted orunsubstituted aryl and substituted or unsubstituted heteroaryl, orR⁷ and R³ are taken together with the nitrogen atom therebetween to forma 3- to 7-membered heterocyclic ring optionally including 1 to 2additional ring heteromoieties selected from O, S, S(O), SO₂, N andNR¹³,wherein said C₃-C₇cycloalkyl and 3- to 7-membered heterocyclic ring areeach further optionally substituted with a substituent selected fromhalogen, CO₂R¹³, C(O)N(R¹³)₂, SO₂R¹³, C₁-C₆alkyl, C₁-C₆haloalkyl,C₂-C₆alkenyl, C₂-C₆haloalkenyl, C₂-C₆alkynyl, C₂-C₆haloalkynyl,C₃-C₆cycloalkyl and a 3- to 6-membered heterocyclic ring including 1 to2 ring heteromoieties selected from O, S, N, S(O), SO₂ and NR¹³;R⁹, R¹⁰ and R¹¹ are independently selected from hydrogen, halogen, CN,OR¹³, N(R¹³)₂, SR¹³, C₁-C₆alkyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl,CO₂R¹³, C(O)N(R¹³)₂, SOR¹³, SO₂R¹³, C₂-C₆alkenyl, C₂-C₆alkynyl,C₂-C₆haloalkynyl, C₃-C₇cycloalkyl and a 3- to 7-membered heterocyclicring including 1 to 2 ring heteromoieties selected from O, S, S(O), SO₂,N and NR¹³, wherein said C₁-C₆alkyl, C₁-C₆haloalkyl, C₂-C₆alkenyl,C₂-C₆haloalkenyl, C₂-C₆alkynyl, C₂-C₆haloalkynyl, C₃-C₆cycloalkyl and 3-to 7-membered heterocyclic ring groups are optionally substituted by oneor more substituents independently selected from CN, OR¹³, N(R¹³)₂ andSR¹³, and wherein said C₃-C₆cycloalkyl and 3- to 7-membered heterocyclicring are each further optionally substituted with a substituent selectedfrom halogen, CO₂R¹³, C(O)N(R¹³)₂, SO₂R¹³, C₁-C₆alkyl, C₁-C₆haloalkyl,C₂-C₆alkenyl, C₂-C₆haloalkenyl, C₂-C₆alkynyl, C₂-C₆haloalkynyl,C₃-C₆cycloalkyl and a 3- to 6-membered heterocyclic ring including 1 to2 ring heteromoieties selected from O, S, S(O), SO₂, N and NR¹³;Y is selected from halogen and X-A;X is selected from O, NR¹³, S, S(O) and SO₂;A is selected from hydrogen, C₁-C₁₀alkyl, C₂-C₁₀alkenyl, C₂-C₁₀alkynyl,C₃-C₆cycloalkyl, C₄-C₆cycloalkenyl, heterocycloalkyl, aryl, heteroaryland P(O)(OR¹²)₂;each R¹² is independently selected from hydrogen, substituted orunsubstituted C₁-C₆alkyl, substituted or unsubstituted C₂-C₆alkenyl,substituted or unsubstituted C₂-C₆alkynyl, substituted or unsubstitutedC₁-C₆haloalkyl, substituted or unsubstituted C₃-C₇cycloalkyl,substituted or unsubstituted C₃-C₇heterocycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted C₁-C₆alkyleneC₃-C₇cycloalkyl, substituted orunsubstituted C₁-C₆alkyleneC₃-C₇heterocycloalkyl, substituted orunsubstituted C₁-C₆alkylenearyl, and substituted or unsubstitutedC₁-C₆alkyleneheteroaryl;each R¹³ is independently selected from hydrogen, C₁-C₆alkyl,C₁-C₆haloalkyl, C₂-C₆alkenyl, C₂-C₆haloalkenyl, C₂-C₆alkynyl,C₂-C₆haloalkynyl, C₃-C₆cycloalkyl, and a 3- to 7-membered heterocyclicring including 1 to 2 ring heteromoieties selected from O, S, S(O), SO₂,N and NR¹⁴, wherein said C₁-C₆alkyl, C₁-C₆haloalkyl, C₂-C₆alkenyl,C₂-C₆haloalkenyl, C₂-C₆alkynyl, C₂-C₆haloalkynyl, C₃-C₆cycloalkyl and 3-to 7-membered heterocyclic ring groups are optionally substituted by oneor more substituents independently selected from CN, OR¹⁴, N(R¹⁴)₂ andSR¹⁴, and wherein said C₃-C₆cycloalkyl and 3- to 7-membered heterocyclicring are each further optionally substituted with a substituent selectedfrom halogen, CO₂R¹⁴, C(O)N(R¹⁴)₂, SO₂R¹⁴, C₁-C₆alkyl, C₁-C₆haloalkyl,C₂-C₆alkenyl, C₂-C₆haloalkenyl, C₂-C₆alkynyl, C₂-C₆haloalkynyl,C₃-C₆cycloalkyl and a 3- to 6-membered heterocyclic ring including 1 to2 ring heteromoieties selected from O, S, S(O), SO₂, N and NR¹⁴,R¹⁴ is selected from hydrogen, substituted or unsubstituted C₁-C₆alkyl,substituted or unsubstituted C₂-C₆alkenyl, substituted or unsubstitutedC₂-C₆alkynyl, substituted or unsubstituted C₁-C₆haloalkyl, substitutedor unsubstituted C₃-C₇cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl and substituted orunsubstituted heteroaryl;wherein at least one of R³, R⁴, R⁵ and R⁶ is deuterium or at least oneof R³, R⁴, R⁵ and R⁶ comprises deuterium, andwherein all available hydrogen atoms are optionally substituted with ahalogen atom and/or all available atoms are optionally substituted withan alternate isotope thereof.

The present application includes a compound of Formula (I) or apharmaceutically acceptable salt, solvate and/or prodrug thereof:

wherein:R¹ is selected from the group consisting of hydrogen, C₁-C₃ alkyl,—(CH₂)P(O)(OR¹²); CO(R¹²), COO(R¹²), C(O)N(R¹²)₂, SO(R¹²) and SO₂(R¹²);R² to R⁶ are independently selected from the group consisting ofhydrogen and lower alkyl;R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl, R⁷ andR⁸ may be taken together with the atoms to which they are attached forma 3- or 7-membered heterocyclic ring including 1 to 2 ring membersselected from the group consisting of O, S, SO₂, N, and N(R¹³) whereinsaid C₃-C₇ cycloalkyl and 3 to 7-membered heterocyclic ring are eachfurther optionally substituted with a member of the group consisting ofC₁-C₃ alkyl and C₁-C₃ haloalkyl, halogen, CN, OR¹³, N(R¹³)₂, COOR¹³,C(O)N(R¹³)₂, SR6, SO₂R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl,C₂-C₆ haloalkenyl, C₂-C₆ alkynyl, C₂-C₆ haloalkynyl, C₃-C₆ cycloalkyl,and a 3- to 6-membered heterocyclic ring including 1 to 2 ring membersselected from the group consisting of O, S, N, and N(R¹³), wherein saidC₁-C₆ alkyl, C₂-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ haloalkenyl;R⁹, R¹⁰ and, R¹¹ are independently selected from the group consisting ofhydrogen, halogen, CN, OR¹³, N(R¹³)₂, SR¹³, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkyl substituted by OR¹³, C₁-C₆ alkyl substituted bySR¹³, C₁-C₆ alkyl substituted by N(R¹³)₂, C₂-C₆ haloalkyl, COOR¹³,C(O)N(R¹³)₂, SO₂R¹³, COOR¹³, C(O)N(R¹³)₂, SO₂R¹³, C₁-C₆ alkyl, C₂-C₆,alkenyl, C₂-C₆ haloalkenyl, C₂-C₆ alkynyl, C₂-C₆ haloalkynyl, C₃-C₇cycloalkyl, and a 3- to 67-membered heterocyclic ring including 1 to 2ring members selected from the group consisting of O, S, N, and N(R¹³),wherein said C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆haloalkenyl, C₂-C₆ alkynyl, C₂-C₆ haloalkynyl, C₃-C₇ cycloalkyl, and 3-to 7-membered heterocyclic ring groups are optionally substituted by oneor more substituents independently selected from the group consisting ofCN, OR¹³, N(R¹³)₂, and SR¹³, and wherein said C₃-C₇ cycloalkyl and 3- to7-membered heterocyclic ring are each further optionally substitutedwith a member of the group consisting of C₁-C₃ alkyl and C₁-C₃haloalkyl, halogen, CN, OR¹³, N(R¹³)₂, COOR¹³, C(O)N(R¹³)₂, SR¹³,SO₂R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ haloalkenyl,C₂-C₆ alkynyl, C₂-C₆ haloalkynyl, C₃-C₆ cycloalkyl, and a 3- to6-membered heterocyclic ring including 1 to 2 ring members selected fromthe group consisting of O, S, N, and N(R¹³), wherein said C₁-C₆ alkyl,C₂-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ haloalkenyl;X is selected from O, NR¹³, S, SO and SO₂;wherein R¹² is selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted haloalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl;R¹³ is selected from the group consisting of hydrogen, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ haloalkenyl, C₂-C₆ alkynyl, C₂-C₆haloalkynyl, C₃-C₇ cycloalkyl, C₁-C₆ alkyl substituted by OR¹³, C₁-C₆alkyl substituted by SR¹³, C₁-C₆ alkyl substituted by N(HR¹³), N(R¹³)₂,C₂-C₆ haloalkyl, COOR¹³, C(O)N(R¹³)₂, SO₂R¹³, COOR¹³, C₁-C₆ alkyl,C₂-C₆, alkenyl, C₂-C₆ haloalkenyl, C₂-C₆ alkynyl, C₂-C₆ haloalkynyl,C₃-C₇ cycloalkyl, and a 3- to 7-membered heterocyclic ring including 1to 2 ring members selected from the group consisting of O, S, N, andN(R¹³), wherein said C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆haloalkenyl, C₂-C₆ alkynyl, C₂-C₆ haloalkynyl, C₃-C₇ cycloalkyl, and 3-to 7-membered heterocyclic ring groups are optionally substituted by oneor more substituents independently selected from the group consisting ofCN, OR¹³, N(R¹³)₂, and SR¹³, and wherein said C₃-C₇ cycloalkyl and 3- to7-membered heterocyclic ring are each further optionally substitutedwith a member of the group consisting of C₁-C₃ alkyl and C₁-C₃haloalkyl, halogen, CN, OR¹³, N(R¹³)₂, COOR¹³, C(O)N(R¹³)₂, SR¹³,SO₂R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ haloalkenyl,C₂-C₆ alkynyl, C₂-C₆ haloalkynyl, C₃-C₆ cycloalkyl, and a 3- to6-membered heterocyclic ring including 1 to 2 ring members selected fromthe group consisting of O, S, N, and N(R¹³), wherein said C₁-C₆ alkyl,C₂-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ haloalkenyl; andA is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl,heterocycloalkynyl aryl, heteroaryl, C₀-C₁ P(O)(OR¹²)₂, CO(Q′), COO(Q′),C(O)N(Q′)₂, SO(Q′), SO₂(Q′), wherein Q′ is selected from hydrogen,C₁-C₂₀ alkyl, C₁-C₂₀ haloalkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ haloalkenyl,C₂-C₂₀ alkynyl, C₂-C₂₀ haloalkynyl, C₃-C₇ cycloalkyl, and a 3- to7-membered heterocyclic ring including 1 to 2 ring members selected fromthe group consisting of O, S, N, and N(R¹³), wherein said C₁-C₂₀ alkyl,C₂-C₂₀ haloalkyl, C₂-C₆ alkenyl, C₂-C₂₀ haloalkenyl, C₃-C₇ cycloalkyl,and 3- to 7-membered heterocyclic ring groups are optionally substitutedby one or more substituents independently selected from the groupconsisting of CN, OR¹³, N(R¹³)₂, and SR¹³, and wherein saidC₃-C₇cycloalkyl and 3- to 7-membered heterocyclic ring are each furtheroptionally substituted with a member of the group consisting of C₁-C₃alkyl and C₁-C₃ haloalkyl; andwherein R¹² and R¹³ are independently defined as above.

In some embodiments, when, in the compounds of Formula I, all availablehydrogen atoms in a group are optionally replaced with a halogen atom,the halogen atom is F, Cl or Br. In some embodiments, when all availablehydrogen atoms in a group are optionally replaced with a halogen atom,the halogen atom is F or Br. In some embodiments, when all availablehydrogen atoms in a group are optionally replaced with a halogen atom,the halogen atom is F.

Therefore, in some embodiments, all available hydrogen atoms areoptionally substituted with a fluorine, chlorine or bromine atom and/orall available atoms are optionally substituted with an alternate isotopethereof. In some embodiments, all available hydrogen atoms areoptionally substituted with a halogen or bromine atom and/or allavailable atoms are optionally substituted with an alternate isotopethereof. In some embodiments, all available hydrogen atoms areoptionally substituted with a halogen or chlorine atom and/or allavailable atoms are optionally substituted with an alternate isotopethereof. In some embodiments, all available hydrogen atoms areoptionally substituted with a halogen atom and/or all available atomsare optionally substituted with an alternate isotope thereof. In someembodiments, all available hydrogen atoms are optionally substitutedwith a halogen atom and/or all available hydrogen atoms are optionallysubstituted with deuterium. In some embodiments, all available hydrogenatoms are optionally substituted with a fluorine atom and/or allavailable atoms are optionally substituted with deuterium. In someembodiments, all available atoms are optionally substituted withdeuterium.

In some embodiments, all available hydrogen atoms are optionallysubstituted with an alternate isotope thereof. In some embodiments, thealternate isotope of hydrogen is deuterium. Accordingly, in someembodiments, the compounds of the application are isotopically enrichedwith deuterium. In some embodiments, one or more of A, X, R¹, R², R³,R⁴, R⁵, R⁶, R⁷ R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ comprises one or moredeuterium or one or more of A, X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷ R⁸, R⁹,R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ is deuterium.

In some embodiments, R¹ is selected from hydrogen, C₁-C₃alkyl, C(O)R¹²,CO₂R¹², C(O)N(R¹²)₂, S(O)R¹² and SO₂R¹²; wherein all available hydrogenatoms are optionally substituted with a halogen and/or all availableatoms are optionally substituted with an alternate isotope thereof. Insome embodiments, R¹ is selected from S(O)R¹² and SO₂R¹², wherein allavailable hydrogen atoms are optionally substituted with a halogenand/or all available atoms are optionally substituted with an alternateisotope thereof. In some embodiments, R¹ is selected from hydrogen,C₁-C₃alkyl, C(O)R¹², CO₂R¹² and C(O)N(R¹²)₂, wherein all availablehydrogen atoms are optionally substituted with a halogen and/or allavailable atoms are optionally substituted with an alternate isotopethereof. In some embodiments, R¹ is selected from hydrogen, C₁-C₃alkyl,C(O)R¹² and CO₂R¹², wherein all available hydrogen atoms are optionallysubstituted with a halogen and/or all available atoms are optionallysubstituted with an alternate isotope thereof. In some embodiments, R¹is selected from hydrogen, CH₃, CH₂CH₃, and CH(CH₃)₂, wherein allavailable hydrogen atoms are optionally substituted with a halogenand/or all available atoms are optionally substituted with an alternateisotope thereof. In some embodiments, R¹ is selected from hydrogen,deuterium, Br, F, CH₃, CF₃, CD₃, CH₂CH₃, CD₂CD₃, CF₂CF₃, CH(CH₃)₂,CD(CD₃)₂, CF(CF₃)₂, C(CD₃)₃, C(CF₃)₃, and C(CH₃)₂. In some embodiments,R¹ is selected from hydrogen, deuterium, CH₃, CF₃ and CD₃. In someembodiments, R¹ is hydrogen.

In some embodiments, R² is selected from hydrogen and C₁-C₄alkyl,wherein all available hydrogen atoms are optionally substituted with ahalogen atom and/or all available atoms are optionally substituted withan alternate isotope thereof. In some embodiments, R² is selected fromhydrogen, CH₃, CH₂CH₃, CH(CH₃)₂ and C(CH₃)₃, wherein all availablehydrogen atoms are optionally substituted with a halogen atom and/or allavailable atoms are optionally substituted with an alternate isotopethereof. In some embodiments, R² is selected from hydrogen, CH₃, CH₂CH₃,CH(CH₃)₂ and C(CH₃)₃, wherein all available hydrogen atoms areoptionally substituted with a halogen atom and/or all available hydrogenatoms are optionally substituted with deuterium. In some embodiments, R²is selected from hydrogen and deuterium, F, Br, CH₃, CF₃, CD₃, CH₂CH₃,CD₂CD₃, CF₂CF₃, CH(CH₃)₂, CD(CD₃)₂, CF(CF₃)₂, C(CD₃)₃, C(CF₃)₃, andC(CH₃)₃. In some embodiments, R² is selected from hydrogen anddeuterium. In some embodiments, R² is hydrogen.

In some embodiments, R³, R⁴, R⁵ and R⁶ are independently selected fromhydrogen and C₁-C₄alkyl, wherein at least one of R³, R⁴, R⁵ and R⁶ isdeuterium or at least one of R³, R⁴, R⁵ and R⁶ comprises deuterium andwherein all available hydrogen atoms are optionally substituted with ahalogen atom and/or all available atoms are optionally substituted withan alternate isotope thereof. In some embodiments, R³, R⁴, R⁵ and R⁶ areindependently selected from hydrogen, CH₃, CH₂CH₃, CH(CH₃)₂ and C(CH₃)₃,wherein all available hydrogen atoms are optionally substituted with ahalogen atom and/or all available atoms are optionally substituted withan alternate isotope thereof and wherein at least one of R³, R⁴, R⁵ andR⁶ is deuterium or at least one of R³, R⁴, R⁵ and R⁶ comprisesdeuterium. In some embodiments, R³, R⁴, R⁵ and R⁶ are independentlyselected from hydrogen, CH₃, CH₂CH₃, CH(CH₃)₂ and C(CH₃)₃, wherein allavailable hydrogen atoms are optionally substituted with a halogen atomand/or all available hydrogen atoms are optionally substituted withdeuterium and wherein at least one of R³, R⁴, R⁵ and R⁶ is deuterium orat least one of R³, R⁴, R⁵ and R⁶ comprises deuterium. In someembodiments, at least one of R³ and R⁴ or R⁵ and R⁶ is deuterium or atleast one of R³ and R⁴ or R⁵ and R⁶ comprises deuterium. In someembodiments, R³, R⁴, R⁵ and R⁶ are independently selected from hydrogen,deuterium, F, Br, CH₃, CD₂H, CDH₂, CD₃, CH₂CH₃, CH₂CH₂D, CH₂CD₂H andCD₂CD₃, wherein at least one of R³, R⁴, R⁵ and R⁶ is deuterium or atleast one of R³, R⁴, R⁵ and R⁶ comprises deuterium. In some embodiments,R³, R⁴, R⁵ and R⁶ are independently selected from hydrogen, deuterium,F, CH₃, CD₂H, CDH₂ and CD₃, wherein at least one of R³, R⁴, R⁵ and R⁶ isdeuterium or at least one of R³, R⁴, R⁵ and R⁶ comprises deuterium. Insome embodiments, R³, R⁴, R⁵ and R⁶ are independently selected fromhydrogen, deuterium, F, CH₃ and CD₃, wherein at least one of R³, R⁴, R⁵and R⁶ is deuterium or at least one of R³, R⁴, R⁵ and R⁶ comprisesdeuterium. In some embodiments, R³, R⁴, R⁵ and R⁶ are independentlyselected from hydrogen, deuterium, CH₃ and CD₃, wherein at least one ofR³, R⁴, R⁵ and R⁶ is deuterium or at least one of R³, R⁴, R⁵ and R⁶comprises deuterium. In some embodiments, at least one of R³, R⁴, R⁵ andR⁶ is F, and wherein at least one of R³, R⁴, R⁵ and R⁶ is deuterium orat least one of R³, R⁴, R⁵ and R⁶ comprises deuterium. In someembodiments, R³, R⁴, R⁵ and R⁶ are independently selected from hydrogen,deuterium and CD₃, wherein at least one of R³, R⁴, R⁵ and R⁶ isdeuterium or at least one of R³, R⁴, R⁵ and R⁶ comprises deuterium. Insome embodiments, at least one of R³ and R⁴ or R⁵ and R⁶ is CD₃. In someembodiments, R³ and R⁴ are both CD₃, or R⁵ and R⁶ are both CD₃. In someembodiments, R³, R⁴, R⁵ and R⁶ are all CD₃. In some embodiments, atleast one of R³ and R⁴ or R⁵ and R⁶ is deuterium. In some embodiments,R³ and R⁴ are both deuterium, or R⁵ and R⁶ are both deuterium. In someembodiments, R³, R⁴, R⁵ and R⁶ are all deuterium.

In some embodiments, R⁷ and R⁸ are independently selected from hydrogen,substituted or unsubstituted C₁-C₄alkyl, substituted or unsubstitutedC₂-C₆alkenyl, substituted or unsubstituted C₂-C₆alkynyl, substituted orunsubstituted C₁-C₄haloalkyl, substituted or unsubstitutedC₃-C₇cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl and substituted or unsubstitutedheteroaryl, wherein all available hydrogen atoms are optionallysubstituted with a halogen atom and/or all available atoms areoptionally substituted with an alternate isotope thereof.

In some embodiments, the C₃-C₇cycloalkyl in R⁷ and R⁸ is independentlyselected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl,wherein all available hydrogen atoms are optionally substituted with ahalogen atom and/or all available atoms are optionally substituted withan alternate isotope thereof.

In some embodiments, the heterocycloalkyl in R⁷ and R⁸ is,independently, a saturated or unsaturated heterocycle. In someembodiments heterocycloalkyl in R⁷ and R⁸ is, independently, a saturatedor unsaturated bridged bicyclic heterocycle. In some embodiments, thesaturated or unsaturated bridged bicyclic heterocycle is independentlyselected from azabicyclohexanyl, diazabicycloheptanyl,oxobicyclohexanyl, oxobicycloheptanyl and oxobicycloheptanenyl, whereinall available hydrogen atoms are optionally substituted with a halogenatom and/or all available atoms are optionally substituted with analternate isotope thereof.

In some embodiments, the heterocycloalkyl in R⁷ and R⁸ independently, asaturated or unsaturated heterocycle. In some embodiments,heterocycloalkyl in R⁷ and R⁸ is, independently, a saturated orunsaturated bridged bicyclic heterocycle. In some embodiments, thesaturated or unsaturated bridged bicyclic heterocycle is independently,selected from azabicyclohexanyl, diazabicycloheptanyl,oxobicyclohexanyl, oxobicycloheptanyl and oxobicycloheptanenyl, whereinall available hydrogen atoms are optionally substituted with a halogenatom and/or all available atoms are optionally substituted with analternate isotope thereof.

In some embodiments, the heterocycloalkyl in R⁷ and R⁸ independentlyselected from aziridinyl, oxiranyl, thiiranyl, oxaxiridinyl, dioxiranyl,azetidinyl, oxetanyl, theitanyl, diazetidinyl, dioxetanyl, dithietanyl,tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl,pyrazolidinyl, isoxthiolidinyl, thiazolidinyl, isothiazolidinyl,dioxolanyl, dithiolanyl, piperidinyl, triazolyl, furazanyl, oxadiazolyl,thiadiazolyl, dioxazolyl, dithiazolyl, tetrazolyl, oxatetrazolyl,tetrahydropyranyl, diazinanyl (e.g, piperazinyl), morpholinyl,thiomorpholinyl, dioxanyl, dithianyl, azepanyl, oxepanyl, thiepanyl anddiazepanyl, wherein all available hydrogen atoms are optionallysubstituted with a halogen atom and/or all available atoms areoptionally substituted with an alternate isotope thereof.

In some embodiments, the heteroaryl in R⁷ and R⁸ is independentlyselected from, azepinyl, benzisoxazolyl, benzofurazanyl, benzopyranyl,benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl,benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl,dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranylsulfone, 1,3-dioxolanyl, furyl, imidazolidinyl, imidazolinyl,imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl,isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl,morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,2-oxopiperazinyl, 2-oxopiperdinyl, 2-oxopyrrolidinyl, piperidyl,piperazinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl,pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl,quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide,thiazolyl, thiazolinyl, thienofuryl, thienothienyl, triazolyl andthienyl, wherein all available hydrogen atoms are optionally substitutedwith a halogen atom and/or all available atoms are optionallysubstituted with an alternate isotope thereof.

In some embodiments, R⁷ and R⁸ are independently selected from hydrogen,C₁-C₄alkyl and C₂-C₆alkenyl, wherein all available hydrogen atoms areoptionally substituted with a halogen atom and/or all available atomsare optionally substituted with an alternate isotope thereof. In someembodiments, R⁷ and R⁸ are independently selected from hydrogen andC₁-C₄alkyl, wherein all available hydrogen atoms are optionallysubstituted with a halogen atom and/or all available atoms areoptionally substituted with an alternate isotope thereof. In someembodiments, R⁷ and R⁸ are independently from hydrogen and C₁-C₄alkyl,wherein all available hydrogen atoms are optionally substituted with ahalogen atom and/or all available hydrogen atoms are optionallysubstituted with deuterium. In some embodiments, R⁷ and R⁸ areindependently selected from hydrogen, deuterium, F, Br, CH₃, CF₃, CD₂H,CDH₂, CD₃, CH₂CH₃, CF₂CF₃, and CD₂CD₃. In some embodiments, R⁷ and R⁸are independently selected from hydrogen, deuterium, CH₃, CD₂H, CDH₂,CD₃, CH₂CH₃ and CD₂CD₃. In some embodiments, R⁷ and R⁸ are independentlyselected from hydrogen, deuterium, CH₃, CD₃, CH₂CH₃ and CD₂CD₃. In someembodiments, R⁷ and R⁸ are independently selected from CH₃, CD₃, CH₂CH₃and CD₂CD₃. In some embodiments, R⁷ and R³ are both CH₃, CD₃, CH₂CH₃ orCD₂CD₃. In some embodiments, R⁷ and R⁸ are both CH₃. In someembodiments, R⁷ and R⁸ are both CDs. In some embodiments, R⁷ and R⁸ areboth CH₂CH₃. In some embodiments, R⁷ and R⁸ are both CD₂CD₃.

In some embodiments, R⁷ and R⁸ are taken together with the nitrogen atomtherebetween to form a 3- to 7-membered heterocyclic ring optionallyincluding 1 to 2 additional ring heteromoieties selected from O, S,S(O), SO₂, N and NR¹³, wherein all available hydrogen atoms areoptionally substituted with a halogen atom and/or all available atomsare optionally substituted with an alternate isotope thereof. In someembodiments, R⁷ and R⁸ are taken together with the nitrogen atomtherebetween to form a 4- to 7-membered heterocyclic ring optionallyincluding 1 to 2 additional ring heteromoieties selected from O, S,S(O), SO₂, N and NR¹³, wherein all available hydrogen atoms areoptionally substituted with a halogen atom and/or all available atomsare optionally substituted with an alternate isotope thereof. In someembodiments, R⁷ and R⁸ may be taken together with the nitrogen atomtherebetween to form azetidinyl, diazetidinyl, pyrrolidinyl,imidazolidinyl, pyrazolidinyl, thiazolidinyl, isothiozolidinyl,piperidinyl, diazinanyl (e.g. piperazinyl), morpholinyl or azepanylring, wherein all available hydrogen atoms are optionally substitutedwith a halogen atom and/or all available atoms are optionallysubstituted with an alternate isotope thereof. In some embodiments, R⁷and R⁸ are taken together with the nitrogen atom therebetween to formpyrrolidinyl, piperidinyl or diazinanyl, wherein all available hydrogenatoms are optionally substituted with a halogen atom and/or allavailable atoms are optionally substituted with an alternate isotopethereof. In some embodiments, R⁷ and R⁸ are taken together with thenitrogen atom therebetween to form pyrrolidinyl, piperidinyl ordiazinanyl, wherein all available hydrogen atoms are optionallysubstituted with a halogen atom and/or all available hydrogens areoptionally substituted with deuterium. In some embodiments, R⁷ and R⁸are taken together with the nitrogen atom therebetween to formpyrrolidinyl, piperidinyl or diazinanyl, wherein all available hydrogensare optionally substituted with deuterium.

When R⁷ and R⁸ are substituted, in some embodiments, the substituentsare independently selected from one or more of Br, Cl, F, CO₂H, CO₂CH₃,C(O)NH₂, C(O)N(CH₃)₂, C(O)NHCH₃, SO₂CH₃, C₁-C₄alkyl, C₁-C₄fluoralkyl,C₂-C₆alkenyl, C₂-C₆fluoroalkenyl, C₂-C₆alkynyl, C₂-C₆fluoroalkynyl,C₃-C₆cycloalkyl and a 3- to 6-membered heterocyclic ring including 1 to2 ring heteromoieties selected from O, S, S(O), SO₂, N, NH and NCH₃. Insome embodiments, the substituents on R⁷ and R⁸ are independentlyselected from one to three of Br, Cl, F, C₁-C₄alkyl, C₁-C₄fluoralkyl,C₂-C₆alkenyl, C₂-C₆fluoroalkenyl, C₂-C₆alkynyl and C₂-C₆fluoroalkynyl.In some embodiments, the substituents on R⁷ and R⁸ are independentlyselected from one or two of Br, Cl, F, CH₃ and CF₃.

In some embodiments, R⁹, R¹⁰ and R¹¹ are independently selected fromhydrogen, halogen, CN, OR¹³, N(R¹³)₂, SR¹³, C₁-C₄alkyl, C₁-C₄haloalkyl,C₂-C₆haloalkenyl, CO₂R¹³, C(O)N(R¹³)₂, S(O)R¹³, SO₂R¹³, C₂-C₆alkenyl,C₂-C₆alkynyl, C₂-C₆haloalkynyl, C₃-C₇cycloalkyl and a 3- to 7-memberedheterocyclic ring including 1 to 2 ring heteromoieties selected from O,S, S(O), SO₂, N and NR¹³, wherein said C₁-C₄alkyl, C₁-C₄haloalkyl,C₂-C₆alkenyl, C₂-C₆haloalkenyl, C₂-C₆alkynyl, C₂-C₆haloalkynyl,C₃-C₇cycloalkyl and 3- to 7-membered heterocyclic ring groups areoptionally substituted by one or more substituents independentlyselected from CN, OR¹³, N(R¹³)₂ and SR¹³ and wherein saidC₃-C₇cycloalkyl and 3- to 7-membered heterocyclic ring are each furtheroptionally substituted with a substituent selected from halogen, CO₂R¹³,C(O)N(R¹³)₂, SO₂R¹³, C₁-C₄alkyl, C₁-C₄haloalkyl, C₂-C₆alkenyl,C₂-C₆haloalkenyl, C₂-C₆alkynyl, C₂-C₆haloalkynyl, C₃-C₆cycloalkyl and a3- to 6-membered heterocyclic ring including 1 to 2 ring heteromoietiesselected from O, S, S(O), SO₂, N and NR¹³; wherein all availablehydrogen atoms are optionally substituted with a halogen atom and/or allavailable atoms are optionally substituted with an alternate isotopethereof.

In some embodiments, R⁹, R¹⁰ and R¹¹ are independently selected fromhydrogen, halogen, CN, OR¹³, N(R¹³)₂, SR¹³, C₁-C₄alkyl, C₁-C₄haloalkyl,C₂-C₆haloalkenyl, CO₂R¹³, C(O)N(R¹³)₂, S(O)R¹³, SO₂R¹³, C₂-C₆alkenyl,C₂-C₆alkynyl and C₂-C₆haloalkynyl, wherein said C₁-C₄alkyl,C₁-C₄haloalkyl, C₂-C₆alkenyl, C₂-C₆haloalkenyl, C₂-C₆alkynyl andC₂-C₆haloalkynyl groups are optionally substituted by one or moresubstituents independently selected from CN, OR¹³, N(R¹³)₂ and SR¹³, andwherein all available hydrogen atoms are optionally substituted with ahalogen atom and/or all available atoms are optionally substituted withan alternate isotope thereof. In some embodiments, R⁹, R¹⁰ and R¹¹ areindependently selected from hydrogen, F, Cl, Br, CN, OR¹³, N(R¹³)₂,SR¹³, C₁-C₄alkyl, C₁-C₄haloalkyl, C₂-C₆haloalkenyl, CO₂R¹³, C(O)N(R¹³)₂,S(O)R¹³, SO₂R¹³, C₂-C₆alkenyl, C₂-C₆alkynyl and C₂-C₆haloalkynyl,wherein said C₁-C₄alkyl, C₁-C₄haloalkyl, C₂-C₆alkenyl, C₂-C₆haloalkenyl,C₂-C₆alkynyl and C₂-C₆haloalkynyl groups are optionally substituted byone to three substituents independently selected from CN, OR¹³, N(R¹³)₂and SR¹³, wherein all available hydrogen atoms are optionallysubstituted with a halogen atom and/or all available atoms areoptionally substituted with an alternate isotope thereof. In someembodiments, R⁹, R¹⁰ and R¹¹ are independently selected from hydrogen,F, Cl, Br, CN, OR¹³, N(R¹³)₂, SR¹³, CH₃, CH₂CH₃, CH(CH₃)₂, C(CH₃)₃,C₁-C₄haloalkyl, C₂-C₆haloalkenyl, CO₂R¹³, S(O)R¹³, SO₂R¹³, C(O)N(R¹³)₂,C₂-C₆alkenyl and C₂-C₆alkynyl, wherein said C₁-C₄alkyl, C₁-C₄haloalkyl,C₂-C₆alkenyl, C₂-C₆haloalkenyl and C₂-C₆alkynyl groups are optionallysubstituted by one or two substituents independently selected from CN,OR¹³, N(R¹³)₂ and SR¹³, wherein all available hydrogen atoms areoptionally substituted with a halogen atom and/or all available atomsare optionally substituted with an alternate isotope thereof. In someembodiments, R⁹, R¹⁰ and R¹¹ are independently selected from hydrogen,F, Cl, Br, CN, OR¹³, N(R¹³)₂, SR¹³, CH₃, CH₂CH₃, CH(CH₃)₂, C(CH₃)₃,C₁-C₄haloalkyl, C₂-C₆haloalkenyl, CO₂R¹³, S(O)R¹³, SO₂R¹³ andC₂-C₆alkenyl, wherein all available hydrogen atoms are optionallysubstituted with a halogen atom and/or all available atoms areoptionally substituted with an alternate isotope thereof. In someembodiments, R⁹, R¹⁰ and R¹¹ are independently selected from hydrogen,F, Cl, Br and CN wherein all available hydrogen atoms are optionallysubstituted with a halogen atom and/or all available atoms areoptionally substituted with an alternate isotope thereof. In someembodiments, R⁹, R¹⁰ and R¹¹ are independently selected from hydrogen,deuterium, F, Cl, Br and CN. In some embodiments, R⁹, R¹⁰ and R¹¹ areindependently selected from hydrogen and deuterium. In some embodiments,R⁹, R¹⁰ and R¹¹ are all hydrogen. In some embodiments, R⁹, R¹⁰ and R¹¹are all deuterium. In some embodiments, R¹⁰ is selected from hydrogen,deuterium, F, Cl, Br and CN and R⁹ and R¹¹ are selected from hydrogenand deuterium. In some embodiments, R¹⁰ is selected from hydrogen,deuterium, F and CN and R⁹ and R¹¹ are selected from hydrogen anddeuterium. In some embodiments, R¹⁰ is selected from hydrogen, F and CNand R⁹ and R¹¹ are selected from hydrogen and deuterium. In someembodiments, R¹⁰ is selected from hydrogen, F and CN and R⁹ and R¹¹ bothhydrogen.

In some embodiments, the C₃-C₇cycloalkyl in R⁹, R¹⁰ and R¹¹ isindependently selected from cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl, wherein all available hydrogen atoms are optionallysubstituted with a halogen atom and/or all available atoms areoptionally substituted with an alternate isotope thereof.

In some embodiments, the 3- to 7-membered heterocyclic ring in R⁹, R¹⁰and R¹¹ is, independently, a saturated or unsaturated heterocycle. Insome embodiments, the 3 to 7-membered heterocyclic ring in R⁹, R¹⁰ andR¹¹ is, independently, a saturated or unsaturated bridged bicyclicheterocycle. In some embodiments, the saturated or unsaturated bridgedbicyclic heterocycle is independently selected from azabicyclohexanyl,diazabicycloheptanyl, oxobicyclohexanyl, oxobicycloheptanyl andoxobicycloheptanenyl, wherein all available hydrogen atoms areoptionally substituted with a halogen atom and/or all available atomsare optionally substituted with an alternate isotope thereof.

In some embodiments, the 3- to 7-membered heterocyclic ring in R⁹, R¹⁰and R¹¹ is, independently, a saturated or unsaturated heterocycle. Insome embodiments, the 3 to 7-membered heterocyclic ring in R⁹, R¹⁰ andR¹¹ is, independently, a saturated or unsaturated bridged bicyclicheterocycle. In some embodiments, the saturated or unsaturated bridgedbicyclic heterocycle is independently, selected from azabicyclohexanyl,diazabicycloheptanyl, oxobicyclohexanyl, oxobicycloheptanyl andoxobicycloheptanenyl, wherein all available hydrogen atoms areoptionally substituted with a halogen atom and/or all available atomsare optionally substituted with an alternate isotope thereof.

In some embodiments, the 3- to 7-membered heterocyclic ring in R⁹, R¹⁰and R¹¹ is independently selected from aziridinyl, oxiranyl, thiiranyl,oxaxiridinyl, dioxiranyl, azetidinyl, oxetanyl, theitanyl, diazetidinyl,dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl,pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxthiolidinyl,thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl,triazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dioxazolyl,dithiazolyl, tetrazolyl, oxatetrazolyl, tetrahydropyranyl, diazinanyl(e.g, piperazinyl), morpholinyl, thiomorpholinyl, dioxanyl, dithianyl,azepanyl, oxepanyl, thiepanyl and diazepanyl, wherein all availablehydrogen atoms are optionally substituted with a halogen atom and/or allavailable atoms are optionally substituted with an alternate isotopethereof.

In some embodiments, each R¹² is independently selected from hydrogen,substituted or unsubstituted C₁-C₄alkyl, substituted or unsubstitutedC₂-C₆alkenyl, substituted or unsubstituted C₂-C₆alkynyl, substituted orunsubstituted C₁-C₄haloalkyl, substituted or unsubstitutedC₃-C₇cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₁-C₄alkyleneC₃-C₇cycloalkyl,substituted or unsubstituted C₁-C₄alkyleneC₃-C₇heterocycloalkyl,substituted or unsubstituted C₁-C₄alkylenearyl and substituted orunsubstituted C₁-C₄alkyleneheteroaryl, wherein all available hydrogenatoms are optionally substituted with a halogen atom and/or allavailable atoms are optionally substituted with an alternate isotopethereof.

In some embodiments, the C₃-C₇cycloalkyl in each R¹² is independentlyselected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl,wherein all available hydrogen atoms are optionally substituted with ahalogen atom and/or all available atoms are optionally substituted withan alternate isotope thereof.

In some embodiments, the heterocycloalkyl in each R¹² is independently asaturated or unsaturated heterocycle. In some embodimentsheterocycloalkyl in each R¹² is independently a saturated or unsaturatedbridged bicyclic heterocycle. In some embodiments, the saturated orunsaturated bridged bicyclic heterocycle is independently selected fromazabicyclohexanyl, diazabicycloheptanyl, oxobicyclohexanyl,oxobicycloheptanyl and oxobicycloheptanenyl, wherein all availablehydrogen atoms are optionally substituted with a halogen atom and/or allavailable atoms are optionally substituted with an alternate isotopethereof.

In some embodiments, the heterocycloalkyl in each R¹² is independentlyselected from aziridinyl, oxiranyl, thiiranyl, oxaxiridinyl, dioxiranyl,azetidinyl, oxetanyl, theitanyl, diazetidinyl, dioxetanyl, dithietanyl,tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl,pyrazolidinyl, isoxthiolidinyl, thiazolidinyl, isothiazolidinyl,dioxolanyl, dithiolanyl, piperidinyl, triazolyl, furazanyl, oxadiazolyl,thiadiazolyl, dioxazolyl, dithiazolyl, tetrazolyl, oxatetrazolyl,tetrahydropyranyl, diazinanyl (e.g, piperazinyl), morpholinyl,thiomorpholinyl, dioxanyl, dithianyl, azepanyl, oxepanyl, thiepanyl anddiazepanyl, wherein all available hydrogen atoms are optionallysubstituted with a halogen atom and/or all available atoms areoptionally substituted with an alternate isotope thereof.

In some embodiments, the heteroaryl in each R¹² is independentlyselected from, azepinyl, benzisoxazolyl, benzofurazanyl, benzopyranyl,benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl,benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl,dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranylsulfone, 1,3-dioxolanyl, furyl, imidazolidinyl, imidazolinyl,imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl,isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl,morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,2-oxopiperazinyl, 2-oxopiperdinyl, 2-oxopyrrolidinyl, piperidyl,piperazinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl,pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl,quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide,thiazolyl, thiazolinyl, thienofuryl, thienothienyl, triazolyl andthienyl, wherein all available hydrogen atoms are optionally substitutedwith a halogen atom and/or all available atoms are optionallysubstituted with an alternate isotope thereof.

In some embodiments, each R¹² is independently selected from hydrogen,C₁-C₄alkyl and C₂-C₆alkenyl, wherein all available hydrogen atoms areoptionally substituted with a halogen atom and/or all available atomsare optionally substituted with an alternate isotope thereof. In someembodiments, each R¹² is independently selected from hydrogen andC₁-C₄alkyl, wherein all available hydrogen atoms are optionallysubstituted with a halogen atom and/or all available atoms areoptionally substituted with an alternate isotope thereof. In someembodiments, each R¹² is independently selected from hydrogen andC₁-C₄alkyl, wherein all available hydrogen atoms are optionallysubstituted with a halogen atom and/or all available hydrogen atoms areoptionally substituted with deuterium. In some embodiments, R¹² isselected from hydrogen, deuterium, CHs, CD₂H, CDH₂, CD₃, CH₂CH₃ andCD₂CD₃. In some embodiments, each R¹² is independently selected fromhydrogen, deuterium, CH₃, CD₃, CH₂CH₃ and CD₂CD₃. In some embodiments,each R¹² is independently selected from hydrogen, CH₃, CD₃, CH₂CH₃ andCD₂CD₃. In some embodiments, each R¹² in R¹ and/or A are both CH₃. Insome embodiments, each R¹² in R¹ and/or A are both CDs. In someembodiments, each R¹² in R¹ and/or in A are both CH₂CH₃. In someembodiments, each R¹² in R¹ and/or in A are both CD₂CD₃. In someembodiments, each R¹² in R¹ and/or in A are both CH₂CH₃. In someembodiments, each R¹² in R¹ and/or in A are both hydrogen.

In some embodiments, each R¹² is independently selected from substitutedor unsubstituted C₁-C₄alkyleneC₃-C₇cycloalkyl, substituted orunsubstituted C₁-C₄alkyleneC₃-C₇heterocycloalkyl, substituted orunsubstituted C₁-C₄alkylenearyl, substituted or unsubstitutedC₁-C₄alkyleneheteroaryl, wherein all available hydrogen atoms areoptionally substituted with a halogen atom and/or all available atomsare optionally substituted with an alternate isotope thereof. In someembodiments, each R¹² is independently selected from substituted orunsubstituted C₁-C₄alkylenearyl and substituted or unsubstitutedC₁-C₄alkyleneheteroaryl, wherein all available hydrogen atoms areoptionally substituted with a halogen atom and/or all available atomsare optionally substituted with an alternate isotope thereof. In someembodiments, each R¹² is independently substituted or unsubstitutedC₁-C₄alkylenearyl wherein all available hydrogen atoms are optionallysubstituted with a halogen atom and/or all available atoms areoptionally substituted with an alternate isotope thereof. In someembodiments, each R¹² is independently substituted or unsubstitutedCH₂aryl wherein all available hydrogen atoms are optionally substitutedwith a halogen atom and/or all available atoms are optionallysubstituted with an alternate isotope thereof. In some embodiments, eachR¹² is independently substituted or unsubstituted CH₂phenyl.

When R¹² is substituted, in some embodiments, the substituents areindependently selected from one or more of Br, Cl, F, CO₂H, CO₂CH₃,C(O)NH₂, C(O)N(CH₃)₂, C(O)NHCH₃, SO₂CH₃, C₁-C₄alkyl, C₁-C₄fluoralkyl,C₂-C₆alkenyl, C₂-C₆fluoroalkenyl, C₂-C₆alkynyl, C₂-C₆fluoroalkynyl,C₃-C₆cycloalkyl and a 3- to 6-membered heterocyclic ring including 1 to2 ring heteromoieties selected from O, S, S(O), SO₂, N, NH and NCH₃. Insome embodiments, the substituents on R¹² are independently selectedfrom one to three of Br, Cl, F, C₁-C₄alkyl, C₁-C₄fluoralkyl,C₂-C₆alkenyl, C₂-C₆fluoroalkenyl, C₂-C₆alkynyl and C₂-C₆fluoroalkynyl.In some embodiments, the substituents on R¹² are independently selectedfrom one or two of Cl, F, CH₃ and CF₃.

In some embodiments, Y is halogen. In some embodiments, the halogen in Yis selected from F, Cl, Br and I. In some embodiments, the halogen in Yis selected from F, Cl and Br. In some embodiments, the halogen in Y isselected from F and Cl. In some embodiments, the halogen in Y is F.

In some embodiments, Y is X-A.

In some embodiments, X is selected from S, S(O) and SO₂. In someembodiments, X is selected from O, NR¹³ and S, wherein all availablehydrogen atoms are optionally substituted with a halogen atom and/or allavailable atoms are optionally substituted with an alternate isotopethereof. In some embodiments, X is selected from NR¹³ and O. In someembodiments, X is O.

In some embodiments, A is selected from hydrogen, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₇cycloalkyl, C₄-C₆cycloalkenyl,heterocycloalkyl, aryl, heteroaryl and P(O)(OR¹²)₂, wherein allavailable hydrogen atoms are optionally substituted with a halogen atomand/or all available atoms are optionally substituted with an alternateisotope thereof. In some embodiments, A is selected from hydrogen,C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₇cycloalkyl,C₄-C₆cycloalkenyl, heterocycloalkyl, aryl and heteroaryl, wherein allavailable hydrogen atoms are optionally substituted with a halogen atomand/or all available atoms are optionally substituted with an alternateisotope thereof. In some embodiments, A is selected from hydrogen,C₁-C₄alkyl and C₂-C₆alkenyl, wherein all available hydrogen atoms areoptionally substituted with a halogen atom and/or all available atomsare optionally substituted with an alternate isotope thereof. In someembodiments, A selected from hydrogen and C₁-C₄alkyl wherein allavailable hydrogen atoms are optionally substituted with a halogen atomand/or all available atoms are optionally substituted with an alternateisotope thereof. In some embodiments, A is H. In some embodiments, A isP(O)(OR¹²)₂, wherein all available hydrogen atoms are optionallysubstituted with a halogen atom and/or all available atoms areoptionally substituted with an alternate isotope thereof.

In some embodiments, each R¹³ is independently selected from hydrogen,C₁-C₆alkyl, C₁-C₆haloalkyl, C₂-C₆alkenyl, C₂-C₆haloalkenyl,C₂-C₆alkynyl, C₂-C₆haloalkynyl, C₃-C₇cycloalkyl, and a 3- to 7-memberedheterocyclic ring including 1 to 2 ring heteromoieties selected from O,S, S(O), SO₂, N and NR¹⁴, wherein said C₁-C₆alkyl, C₁-C₆haloalkyl,C₂-C₆alkenyl, C₂-C₆haloalkenyl, C₂-C₆alkynyl, C₂-C₆haloalkynyl,C₃-C₇cycloalkyl and 3- to 7-membered heterocyclic ring groups areoptionally substituted by one or more substituents independentlyselected from CN, OR¹⁴, N(R¹⁴)₂ and SR¹⁴, and wherein saidC₃-C₇cycloalkyl and 3- to 7-membered heterocyclic ring are each furtheroptionally substituted with a substituent selected from halogen, CO₂R¹⁴,C(O)N(R¹⁴)₂, SO₂R¹⁴, C₁-C₆alkyl, C₁-C₆haloalkyl, C₂-C₆alkenyl,C₂-C₆haloalkenyl, C₂-C₆alkynyl, and C₂-C₆haloalkynyl wherein allavailable hydrogen atoms are optionally substituted with a halogen atomand/or all available atoms are optionally substituted with an alternateisotope thereof.

In some embodiments, each R¹³ is independently selected from hydrogen,C₁-C₆alkyl, C₁-C₆haloalkyl, C₂-C₆alkenyl, C₂-C₆haloalkenyl,C₂-C₆alkynyl, C₂-C₆haloalkynyl, C₃-C₇cycloalkyl, and a 3- to 7-memberedheterocyclic ring including 1 to 2 ring heteromoieties selected from O,S, S(O), SO₂, N and N(R¹⁴), wherein all available hydrogen atoms areoptionally substituted with a halogen atom and/or all available atomsare optionally substituted with an alternate isotope thereof.

In some embodiments, each R¹³ is independently selected from hydrogen,C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₇cycloalkyl, and a 3- to7-membered heterocyclic ring including 1 to 2 ring hetermoietiesselected from O, S, S(O), SO₂, N and N(R¹⁴), wherein all availablehydrogen atoms are optionally substituted with a halogen atom and/or allavailable atoms are optionally substituted with an alternate isotopethereof. In some embodiments, each R¹³ is independently selected fromhydrogen, C₁-C₆alkyl, C₂-C₆alkenyl and C₂-C₆alkynyl, wherein allavailable hydrogen atoms are optionally substituted with a halogen atomand/or all available atoms are optionally substituted with an alternateisotope thereof. In some embodiments, each R¹³ is independently selectedfrom hydrogen, C₁-C₆alkyl, C₂-C₆alkenyl and C₂-C₆alkynyl, wherein allavailable hydrogen atoms are optionally substituted with a halogen atomand/or all available hydrogen atoms are optionally substituted withdeuterium. In some embodiments, each R¹³ is independently selected fromhydrogen and C₁-C₆alkyl wherein all available hydrogen atoms areoptionally substituted with a halogen atom and/or all available hydrogenatoms are optionally substituted with deuterium. In some embodiment,each R¹³ is independently selected from hydrogen, deuterium, F, CH₃,CF₃, CD₂H, CDH₂, CD₃, CH₂CH₃, CF₂CF₃, and CD₂CD₃. In some embodiment,each R¹³ is independently selected from hydrogen, deuterium, CH₃, CD₂H,CDH₂, CD₃, CH₂CH₃, and CD₂CD₃. In some embodiment, each R¹³ is hydrogen.In some embodiment, each R¹³ is independently CH₃ or CD₃.

In some embodiments, R¹⁴ is selected from hydrogen, substituted orunsubstituted C₁-C₄alkyl, substituted or unsubstituted C₂-C₆alkenyl,substituted or unsubstituted C₂-C₆alkynyl, substituted or unsubstitutedC₁-C₄haloalkyl, substituted or unsubstituted C₃-C₇cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl and substituted or unsubstituted heteroaryl, whereinall available hydrogen atoms are optionally substituted with a halogenatom and/or all available atoms are optionally substituted with analternate isotope thereof.

In some embodiments, R¹⁴ is selected from hydrogen, C₁-C₄alkyl andC₂-C₆alkenyl, wherein all available hydrogen atoms are optionallysubstituted with a halogen atom and/or all available atoms areoptionally substituted with an alternate isotope thereof. In someembodiments, R¹⁴ is selected from hydrogen and C₁-C₄alkyl, wherein allavailable hydrogen atoms are optionally substituted with a halogen atomand/or all available atoms are optionally substituted with an alternateisotope thereof. In some embodiments, R¹⁴ is selected from hydrogen andC₁-C₄alkyl, wherein all available hydrogen atoms are optionallysubstituted with a halogen atom and/or all available hydrogen atoms areoptionally substituted with deuterium. In some embodiments, R¹⁴ ishydrogen, deuterium, F, Br, CH₃, CF₃, CD₂H, CDH₂, CD₃, CH₂CH₃, CF₂CF₃,and CD₂CD₃. In some embodiments, R¹⁴ is selected is from hydrogen,deuterium, CH₃, CD₂H, CDH₂, CD₃, CH₂CH₃ and CD₂CD₃. In some embodiments,R¹⁴ is selected from hydrogen, deuterium, CH₃ and CD₃. In someembodiments, R¹⁴ is hydrogen.

When R¹⁴ is substituted, in some embodiments, the substituents areindependently selected from one or more of Br, C, F, CO₂H, CO₂CH₃,C(O)NH₂, C(O)N(CH₃)₂, C(O)NHCH₃, SO₂CH₃, C₁-C₄alkyl, C₁-C₄fluoralkyl,C₂-C₆alkenyl, C₂-C₆fluoroalkenyl, C₂-C₆alkynyl, C₂-C₆fluoroalkynyl,C₃-C₆cycloalkyl and a 3- to 6-membered heterocyclic ring including 1 to2 ring heteromoieties selected from O, S, S(O), SO₂, N, NH and NCH₃. Insome embodiments, the substituents on R⁴ are independently selected fromone to three of Br, C, F, C₁-C₄alkyl, C₁-C₄fluoralkyl, C₂-C₆alkenyl,C₂-C₆fluoroalkenyl, C₂-C₆alkynyl and C₂-C₆fluoroalkynyl. In someembodiments, the substituents on R⁴ are independently selected from oneor two of Br, C, F, CH₃ and CF₃.

In some embodiments, when Y is X-A, X is O and A is P(O)(OR¹²)₂ thecompound of Formula (I) is a compound of Formula (I-A). Accordingly, inanother embodiment, the application includes a compound of Formula (I-A)or a pharmaceutically acceptable salt, solvate or prodrug thereof:

wherein:R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are as defined inFormula (I), wherein at least one of R³, R⁴, R⁵ and R⁶ is deuterium orat least one of R³, R⁴, R⁵ and R⁶ comprises deuterium, andwherein all available hydrogen atoms are optionally substituted with ahalogen atom and/or all available atoms are optionally substituted withan alternate isotope thereof.

In some embodiments, when Y is X-A, X is O and A is P(O)(OR¹²)₂, and R⁹and R¹¹ are both H, the compound of Formula (I) is a compound of Formula(I-B). Accordingly, in some embodiments, the application includes acompound of Formula (I-B) or a pharmaceutically acceptable salt, solvateand/or prodrug thereof:

whereinR¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰ and R¹² are as defined in Formula(I),wherein at least one of R³, R⁴, R⁵ and R⁶ is deuterium or at least oneof R³, R⁴, R⁵ and R⁶ comprises deuterium, andwherein all available hydrogen atoms are optionally substituted with ahalogen atom and/or all available atoms are optionally substituted withan alternate isotope thereof.

In some embodiments, when Y is X-A, X is O and A is P(O)(OH)₂, R⁹ and R¹are both H and R¹ is H, the compound of Formula (I) is a compound ofFormula (I-D). Accordingly, in an embodiment, the application includes acompound of Formula (I-D) or a pharmaceutically acceptable salt, solvateand/or prodrug thereof:

wherein:R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R¹⁰ are as defined in Formula (I),wherein at least one of R³, R⁴, R⁵ and R⁶ is deuterium or at least oneof R³, R⁴, R⁵ and R⁶ comprises deuterium, andwherein all available hydrogen atoms are optionally substituted with ahalogen atom and/or all available atoms are optionally substituted withan alternate isotope thereof.

In some embodiments, Y is X-A and the compound of Formula (I) is acompound of Formula (I-H). Accordingly, in some embodiments, theapplication includes a compound of Formula (I-H) or a pharmaceuticallyacceptable salt, solvate and/or prodrug thereof:

wherein:A, X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷ R⁸, R⁹, R¹⁰ and R¹¹ are as defined inFormula (I), andwherein at least one of R³, R⁴, R⁵ and R⁶ is deuterium or at least oneof R³, R⁴, R⁵ and R⁶ comprises deuterium, andwherein all available hydrogen atoms are optionally substituted with ahalogen atom and/or all available atoms are optionally substituted withan alternate isotope thereof.

In some embodiments, Y is halogen and the compound of Formula (I) is acompound of Formula (I-I). Accordingly, in some embodiments, theapplication includes a compound of Formula (I-I) or a pharmaceuticallyacceptable salt, solvate and/or prodrug thereof:

wherein:Y is halogen; andR¹, R², R³, R⁴, R⁵, R⁶, R⁷ R⁸, R⁹, R¹⁰ and R¹ are as defined in Formula(I), andwherein at least one of R³, R⁴, R⁵ and R⁶ is deuterium or at least oneof R³, R⁴, R⁵ and R⁶ comprises deuterium, andwherein all available hydrogen atoms are optionally substituted with ahalogen atom and/or all available atoms are optionally substituted withan alternate isotope thereof.

In some embodiments, in the compounds of Formula (I-I), Y is selectedfrom F, Cl and Br. In some embodiments, in the compounds of Formula(I-I), Y is selected from F and Br. In some embodiments, in thecompounds of Formula (I-I), Y is F.

In some embodiments, Y is X-A and A is C₁₋₆ alkyl and the compound ofFormula (I) is a compound of Formula (I-J). Accordingly, in someembodiments, the application includes a compound of Formula (I-H) or apharmaceutically acceptable salt, solvate and/or prodrug thereof:

wherein:A is C₁₋₆ alkyl; andX, R¹, R², R³, R⁴, R⁵, R⁶, R⁷ R⁸, R⁹, R¹⁰ and R¹¹ are as defined inFormula (I), andwherein all available hydrogen atoms are optionally substituted with ahalogen atom and/or all available atoms are optionally substituted withan alternate isotope thereof.

In some embodiments, A in the compound of Formula (I-J) is selected fromCH₃, CD₂H, CDH₂, CD₃, CH₂CH₃, CH₂CH₂D, CH₂CD₂H and CD₂CD₃. In someembodiments, A in the compound of Formula (I-J) selected from CH₃, CD₃,CH₂CH₃ and CD₂CD₃. In some embodiments, A in the compound of Formula(I-J) selected from CH₃, and CD₃.

In some embodiments, in the compounds of Formula (I-A), (I-B) and (I-H)to (I-J), R¹ is selected from hydrogen, C₁-C₃alkyl, C(O)R¹², CO₂OR¹²,C(O)N(R¹²)₂, S(O)R¹² and SO₂R¹²; wherein all available hydrogen atomsare optionally substituted with a halogen atom and/or all availableatoms are optionally substituted with an alternate isotope thereof. Insome embodiments, in the compounds of Formula (I-A), (I-B) and (I-H) to(I-J), R¹ is selected from hydrogen, C₁-C₃alkyl, C(O)R⁹ and CO₂R⁹,wherein all available hydrogen atoms are optionally substituted with ahalogen atom and/or all available atoms are optionally substituted withan alternate isotope thereof. In some embodiments, in the compounds ofFormula (I-A), (I-B) and (I-H) to (I-J), R¹ is selected from hydrogen,CH₃, CH₂CH₃, and CH(CH₃)₂, wherein all available hydrogen atoms areoptionally substituted with a halogen atom and/or all available atomsare optionally substituted with an alternate isotope thereof. In someembodiments, in the compounds of Formula (I-A), (I-B) and (I-H) to(I-J), R¹ is selected from hydrogen, deuterium, Br, F, CH₃, CF₃, CD₃,CH₂CH₃, CD₂CD₃, CF₂CF₃, CH(CH₃)₂, CD(CD₃)₂, CF(CF₃)₂, C(CD₃)₃, C(CF₃)₃,and C(CH₃)₂, In some embodiments, in the compounds of Formula (I-A),(I-B) and (I-H) to (I-J), R¹ is selected from hydrogen, deuterium, CH₃,CF₃ and CD₃. In some embodiments, in the compounds of Formula(I-A),(I-B) and (I-H) to (I-J), R¹ is hydrogen.

In some embodiments, in the compounds of Formula (I-A), (I-B), (I-D),(I-H) to (I-J), R² is selected from hydrogen and C₁-C₄alkyl, wherein allavailable hydrogen atoms are optionally substituted with a halogen atomand/or all available atoms are optionally substituted with an alternateisotope thereof. In some embodiments, in the compounds of Formula (I-A),(I-B), (I-D), (I-H) to (I-J), R² is selected from hydrogen, CH₃, CH₂CH₃,CH(CH₃)₂ and C(CH₃)₃, wherein all available hydrogen atoms areoptionally substituted with a halogen atom and/or all available hydrogenatoms are optionally substituted with deuterium. In some embodiments, inthe compounds of Formula (I-A), (I-B), (I-D), (I-H) to (I-J), R² isselected from hydrogen and deuterium, F, CH₃, CF₃, CD₃, CH₂CH₃, CD₂CD₃,CF₂CF₃, CH(CH₃)₂, CD(CD₃)₂, CF(CF₃)₂, C(CD₃)₃, C(CF₃)₃, and C(CH₃)₃. Insome embodiments, in the compounds of Formula (I-A), (I-B), (I-D), (I-H)to (I-J), R² is selected from hydrogen and deuterium. In someembodiments, R² is hydrogen.

In some embodiments, in the compounds of Formula (I-A), (I-B), (I-D),(I-H) to (I-J), R³, R⁴, R⁵ and R⁶ are independently selected fromhydrogen and C₁-C₄alkyl, wherein at least one of R³, R⁴, R⁵ and R⁶ isdeuterium or at least one of R³, R⁴, R⁵ and R⁶ comprises deuterium andwherein all available hydrogen atoms are optionally substituted with ahalogen atom and/or all available atoms are optionally substituted withan alternate isotope thereof. In some embodiments, in the compounds ofFormula (I-A), (I-B), (I-D), (I-H) to (I-J), R³, R⁴, R⁵ and R⁶ areindependently selected from hydrogen, CH₃, CH₂CH₃, CH(CH₃)₂ and C(CH₃)₃,wherein all available hydrogen atoms are optionally substituted with ahalogen atom and/or all available hydrogen atoms are optionallysubstituted with deuterium and wherein at least one of R³, R⁴, R⁵ and R⁶is deuterium or at least one of R³, R⁴, R⁵ and R⁶ comprises deuterium.In some embodiments, in the compounds of Formula (I-A), (I-B), (I-D),(I-H) to (I-J), R³, R⁴, R⁵ and R⁶ are independently selected fromhydrogen, deuterium, Br, F, CH₃, CD₂H, CDH₂, CD₃, CH₂CH₃, CH₂CH₂D,CH₂CD₂H and CD₂CD₃, wherein at least one of R³, R⁴, R⁵ and R⁶ isdeuterium or at least one of R³, R⁴, R⁵ and R⁶ comprises deuterium. Insome embodiments, R³, R⁴, R⁵ and R⁶ are independently selected fromhydrogen, deuterium, F, CH₃, CD₂H, CDH₂ and CD₃, wherein at least one ofR³, R⁴, R⁵ and R⁶ is deuterium or at least one of R³, R⁴, R⁵ and R⁶comprises deuterium. In some embodiments, in the compounds of Formula(I-A), (I-B), (I-D), (I-H), to (I-J) R³, R⁴, R⁵ and R⁶ are independentlyselected from hydrogen, deuterium, CH₃ and CD₃, wherein at least one ofR³, R⁴, R⁵ and R⁶ is deuterium or at least one of R³, R⁴, R⁵ and R⁶comprises deuterium. In some embodiments, in the compounds of Formula(I-A), (I-B), (I-D), (I-H) to (I-J), R³, R⁴, R⁵ and R⁶ are independentlyselected from hydrogen, deuterium and CD₃, wherein at least one of R³,R⁴, R⁵ and R⁶ is deuterium or at least one of R³, R⁴, R⁵ and R⁶comprises deuterium. In some embodiments, in the compounds of Formula(I-A), (I-B), (I-D), (I-H) to (I-J) at least one of R³ and R⁴ or R⁵ andR⁶ is CD₃. In some embodiments, in the compounds of Formula (I-A),(I-B), (I-D), (I-H) to (I-J), R³ and R⁴ are both CD₃, or R⁵ and R⁶ areboth CD₃. In some embodiments, in the compounds of Formula (I-A), (I-B),(I-D), (I-H) to (I-J), R³, R⁴, R⁵ and R⁶ are all CD₃. In someembodiments, in the compounds of Formula (I-A), (I-B), (I-D), (I-H) to(I-J), R³ and R⁴ are both deuterium, or R⁵ and R⁶ are both deuterium. Insome embodiments, in the compounds of Formula (I-A), (I-B), (I-D), (I-H)to (I-J), R³, R⁴, R⁵ and R⁶ are all deuterium.

In some embodiments in the compounds of Formula (I-A), (I-B), (I-D),(I-H) to (1-J), R⁷ and R⁸ are independently selected from hydrogen,deuterium, Br, F, CH₃, CF₃, CD₂H, CDH₂, CD₃, CH₂CH₃, CF₂CF₃, and CD₂CD₃.In some embodiments, in the compounds of Formula (I-A), (I-B), (I-D),(I-H) to (I-J), R⁷ and R⁸ are independently selected from hydrogen,deuterium, CH₃, CD₃, CH₂CH₃ and CD₂CD₃. In some embodiments. in thecompounds of Formula (I-A), (I-B), (I-D), (I-H) to (I-J), R⁷ and R⁸ areboth hydrogen, deuterium, CH₃, CD₃, CH₂CH₃ or CD₂CD₃. In someembodiments, in the compounds of Formula (I-A), (I-B), (I-D), (I-H) to(I-J), R⁷ and R⁸ are both hydrogen. In some embodiments, in thecompounds of Formula (I-A), (I-B), (I-D), (I-H) to (I-J), R⁷ and R⁸ areboth CH₃. In some embodiments, in the compounds of Formula (I-A), (I-B),(I-D), (I-H) and (I-K), R⁷ and R⁸ are both CD₃. In some embodiments, inthe compounds of Formula (I-A), (I-B), (I-D), (I-H) to (I-J), R⁷ and R⁸are both CH₂CH₃. In some embodiments, in the compounds of Formula (I-A),(I-B), (I-D), (I-H) to (I-J), R⁷ and R⁸ are both CD₂CD₃.

In some embodiments, in the compounds of Formula (I-A), (I-B), (I-D),(I-H) to (I-J), at least one of R³, R⁴, R⁵ and R⁶ is deuterium or atleast one of R³, R⁴, R⁵ and R⁶ comprises deuterium and R⁷ and R⁸ areindependently selected from hydrogen, deuterium, CH₃, CD₃, CH₂CH₃ andCD₂CD₃. In some embodiments, in the compounds of Formula (I-A), (I-B),(I-D), (I-H) to (I-J), at least one of R³ and R⁴ or R⁵ and R⁶ isdeuterium and R⁷ and R⁸ are both hydrogen, deuterium, CH₃, CD₃, CH₂CH₃or CD₂CD₃. In some embodiments, in the compounds of Formula (I-A),(I-B), (I-D), (I-H) to (I-J), R³, R³, R⁴, R⁵ and R⁶ are all deuteriumand R⁷ and R⁸ are both hydrogen, deuterium, CH₃, CD₃, CH₂CH₃ or CD₂CD₃.

In some embodiments, in the compounds of Formula (I-A), (I-B), (I-D),(I-H) to (I-J), R⁷ and R⁸ are taken together with the nitrogen atomtherebetween to form pyrrolidinyl, piperidinyl or diazinanyl, whereinall available hydrogen atoms are optionally substituted with a halogenatom and/or all available hydrogens are optionally substituted withdeuterium. In some embodiments, in the compounds of Formula (I-A),(I-B), (I-D), (I-H) to (I-J), R³, R⁴, R⁵ and R⁶ are all hydrogen or R³,R⁴, R⁵ and R⁶ are all deuterium and R⁷ and R⁸ are taken together withthe nitrogen atom therebetween to form pyrrolidinyl, piperidinyl ordiazinanyl, wherein all available hydrogen atoms are optionallysubstituted with a halogen atom and/or all available hydrogens areoptionally substituted with deuterium.

In some embodiments, in the compound of Formula (I-A), (I-H) to (I-J),R⁹, R¹⁰ and R¹¹ are independently selected from hydrogen, F, Cl, Br, CN,OR¹³, N(R¹³)₂, SR¹³, CH₃, CH₂CH₃, CH(CH₃)₂, C(CH₃)₃, C₁-C₄haloalkyl,C₂-C₆haloalkenyl, CO₂R¹³, S(O)R¹³, SO₂R¹³ and C₂-C₆alkenyl, wherein allavailable hydrogen atoms are optionally substituted with a halogen atomand/or all available atoms are optionally substituted with an alternateisotope thereof. In some embodiments, in the compound of Formula (I-A),(I-H) to (I-J), R⁹, R¹⁰ and R¹ are independently selected from hydrogen,F, Cl, Br and CN wherein all available hydrogen atoms are optionallysubstituted with a halogen atom and/or all available atoms areoptionally substituted with an alternate isotope thereof. In someembodiments, in the compound of Formula (I-A), (I-H) to (I-J), R⁹, R¹⁰and R¹¹ are independently selected from hydrogen, deuterium, F, Cl, Brand CN. In some embodiments, in the compound of Formula (I-A), (I-H) to(I-J), R⁹, R¹⁰ and R¹¹ are independently selected from hydrogen anddeuterium. In some embodiments, in the compound of Formula (I-A), (I-H)to (I-J), R⁹, R¹⁰ and R¹¹ are all hydrogen. In some embodiments, in thecompound of Formula (I-A), (I-H) to (I-J), R⁹, R¹⁰ and R¹¹ are alldeuterium. In some embodiments, in the compound of Formula (I-A), (I-H)to (I-J), R¹⁰ is selected from hydrogen, deuterium, F, Cl, Br and CN andR⁹ and R¹¹ are selected from hydrogen and deuterium. In someembodiments, in the compound of Formula (I-A), (I-H) to (I-J), R¹⁰ isselected from hydrogen, deuterium, F and CN and R⁹ and R¹¹ are selectedfrom hydrogen and deuterium. In some embodiments, in the compound ofFormula (I-A), (I-H) to (I-J), R¹⁰ is selected from hydrogen, F and CNand R⁹ and R¹¹ are selected from hydrogen and deuterium. In someembodiments, in the compound of Formula (I-A), (I-H) to (I-J), R¹⁰ isselected from hydrogen, F and CN and R⁹ and R¹¹ both hydrogen. In someembodiments, in the compound of Formula (I-A), (I-H) to (I-J), R¹⁰ isselected from hydrogen, deuterium, F, C, Br and CN.

In some embodiments, the compounds of Formula (I) are selected from:

-   3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-yl dihydrogen    phosphate-   2-(4-fluoro-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4-   2-(4-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4;    and-   3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol,    or a pharmaceutically acceptable salt, solvate and/or prodrug    thereof.

In some embodiments, the compound of Formula (I) is:

Chemical Compound Formula/ ID # IUPAC Name Molecular Weight ChemicalStructure I-3  3-(2-(bis(methyl- d3)amino)ethyl- 1,1,2,2-d4)-1H-indol-4-yl dihydrogen phosphate C12H7D10N2O4P 294.31

I-43 2-(4-fluoro-1H- indol-3-yl)-N,N- bis(methyl- d3)ethan-1-amine-1,1,2,2-d4 C12H5D10FN2 216.33

I-44 2-(4-methoxy-1H- indol-3-yl)-N,N- bis(methyl- d3)ethan-1-amine-1,1,2,2-d4 C13H8D10N2O 228.36

I-45 3-(2-(bis(methyl- d3)amino)ethyl- 1,1,2,2-d4)-1H- indol-4-olC12H6D10N2O 214.33

or a pharmaceutically acceptable salt, solvate and/or prodrug thereof.

In another embodiment, the application includes a compound of Formula(IA) or a pharmaceutically acceptable salt, solvate or prodrug thereof:

or a pharmaceutically acceptable salt thereof,wherein R¹ is selected from the group consisting of hydrogen, C₁-C₃alkyl, —(CH₂)P(O)(OR¹²); CO(R¹²), COO(R¹²), C(O)N(R¹²)₂, SO(R¹²) andSO₂(R¹²);R² to R⁶ are independently selected from the group consisting ofhydrogen and lower alkyl;R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl, whereinR⁷ and R⁸ may be taken together with the atoms to which they areattached form a 3- or 7-membered heterocyclic ring including 1 to 2 ringmembers selected from the group consisting of O, S, SO₂, N, and N(R¹³)wherein said C₃-C₇ cycloalkyl and 3- to 7-membered heterocyclic ring areeach further optionally substituted with a member of the groupconsisting of C₁-C₃ alkyl and C₁-C₃ haloalkyl, halogen, CN, OR¹³,N(R¹³)₂, COOR¹³, C(O)N(R¹³)₂, SR6, SO₂R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₂-C₆ alkenyl, C₂-C₆ haloalkenyl, C₂-C₆ alkynyl, C₂-C₆ haloalkynyl,C₃-C₆ cycloalkyl, and a 3- to 6-membered heterocyclic ring including 1to 2 ring members selected from the group consisting of O, S, N, andN(R¹³), wherein said C₁-C₆ alkyl, C₂-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆haloalkenyl;R⁹, R¹⁰, and R¹¹ are independently selected from the group consisting ofhydrogen, halogen, CN, OR¹³, N(R¹³)₂, SR¹³, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkyl substituted by OR¹³, C₁-C₆ alkyl substituted bySR¹³, C₁-C₆ alkyl substituted by N(R¹³)₂, C₂-C₆ haloalkyl, COOR¹³,C(O)N(R¹³)₂, SO₂R¹³, COOR¹³, C(O)N(R¹³)₂, SO₂R¹³, C₁-C₆ alkyl, C₂-C₆,alkenyl, C₂-C₆ haloalkenyl, C₂-C₆ alkynyl, C₂-C₆ haloalkynyl, C₃-C₇cycloalkyl, and a 3- to 7-membered heterocyclic ring including 1 to 2ring members selected from the group consisting of O, S, N, and N(R¹³),wherein said C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆haloalkenyl, C₂-C₆ alkynyl, C₂-C₆ haloalkynyl, C₃-C₇ cycloalkyl, and 3-to 7-membered heterocyclic ring groups are optionally substituted by oneor more substituents independently selected from the group consisting ofCN, OR¹³, N(R¹³)₂, and SR¹³, and wherein said C₃-C₇ cycloalkyl and 3- to7-membered heterocyclic ring are each further optionally substitutedwith a member of the group consisting of C₁-C₃ alkyl and C₁-C₃haloalkyl, halogen, CN, OR¹³, N(R¹³)₂, COOR¹³, C(O)N(R¹³)₂, SR¹³,SO₂R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ haloalkenyl,C₂-C₆ alkynyl, C₂-C₆ haloalkynyl, C₃-C₆ cycloalkyl, and a 3- to6-membered heterocyclic ring including 1 to 2 ring members selected fromthe group consisting of O, S, N, and N(R¹³), wherein said C₁-C₆ alkyl,C₂-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ haloalkenyl;wherein R¹² is selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted haloalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl;R¹³ is selected from the group consisting of hydrogen, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ haloalkenyl, C₂-C₆ alkynyl, C₂-C₆haloalkynyl, C₃-C₇ cycloalkyl, C₁-C₆ alkyl substituted by OR¹³, C₁-C₆alkyl substituted by SR¹³, C₁-C₆ alkyl substituted by N(HR¹³), N(R¹³)₂,C₂-C₆ haloalkyl, COOR¹³, C(O)N(R¹³)₂, SO₂R¹³, COOR¹³, C₁-C₆ alkyl,C₂-C₆, alkenyl, C₂-C₆ haloalkenyl, C₂-C₆ alkynyl, C₂-C₆ haloalkynyl,C₃-C₇ cycloalkyl, and a 3- to 7-membered heterocyclic ring including 1to 2 ring members selected from the group consisting of O, S, N, andN(R¹³), wherein said C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆haloalkenyl, C₂-C₆ alkynyl, C₂-C₆ haloalkynyl, C₃-C₇ cycloalkyl, and 3-to 7-membered heterocyclic ring groups are optionally substituted by oneor more substituents independently selected from the group consisting ofCN, OR¹³, N(R¹³)₂, and SR¹³, and wherein said C₃-C₇ cycloalkyl and 3- to7-membered heterocyclic ring are each further optionally substitutedwith a member of the group consisting of C₁-C₃ alkyl and C₁-C₃haloalkyl, halogen, CN, OR¹³, N(R¹³)₂, COOR¹³, C(O)N(R¹³)₂, SR¹³,SO₂R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ haloalkenyl,C₂-C₆ alkynyl, C₂-C₆ haloalkynyl, C₃-C₆ cycloalkyl, and a 3- to6-membered heterocyclic ring including 1 to 2 ring members selected fromthe group consisting of O, S, N, and N(R¹³), wherein said C₁-C₆ alkyl,C₂-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ haloalkenyl; andA is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloaalkenyl, heterocycloalkyl, heterocycloaalkenyl,heterocycloaalkynyl, heterocycloalkynyl aryl, heteroaryl, C₀-C₁P(O)(OR¹²)₂, CO(Q′), COO(Q′), C(O)N(Q′)₂, SO(Q′), SO₂(Q′), where Q′ isselected from hydrogen, C₁-C₂₀ alkyl, C₁-C₂₀ haloalkyl, C₂-C₂₀ alkenyl,C₂-C₂₀ haloalkenyl, C₂-C₂₀ alkynyl, C₂-C₂₀ haloalkynyl, C₃-C₇cycloalkyl, and a 3- to 7-membered heterocyclic ring including 1 to 2ring members selected from the group consisting of O, S, N, and N(R¹³),wherein said C₁-C₂₀ alkyl, C₂-C₂₀ haloalkyl, C₂-C₆ alkenyl, C₂-C₂₀haloalkenyl, C₃-C₇ cycloalkyl, and 3- to 7-membered heterocyclic ringgroups are optionally substituted by one or more substituentsindependently selected from the group consisting of CN, OR¹³, N(R¹³)₂,and SR¹³, and wherein said C₃-C₇cycloalkyl and 3- to 7-memberedheterocyclic ring are each further optionally substituted with a memberof the group consisting of C₁-C₃ alkyl and C₁-C₃ haloalkyl; andwherein R¹² and R¹³ are independently defined as above.

In one embodiment, the compounds of general formula (I), andpharmaceutically acceptable salts of the foregoing, the compounds areisotopically enriched with deuterium. In aspects of these embodiments,one or more of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³may include deuterium;

In an embodiment, the application includes a compound of Formula (IB) orFormula (1C) or a pharmaceutically acceptable salt, solvate or prodrugthereof:

wherein R¹ is selected from the group consisting of hydrogen, C₁-C₃alkyl, —(CH₂)P(O)(OR¹²); CO(R¹²), COO(R¹²), C(O)N(R¹²)₂, SO(R¹²) andSO₂(R¹²);R² to R⁶ are independently selected from the group consisting ofhydrogen and lower alkyl;R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl, whereinR⁷ and R⁸ may be taken together with the atoms to which they areattached form a 3- or 7-membered cyclic or heterocyclic ring;R¹⁰ is selected from the group consisting of hydrogen, halogen, CN,OR¹³, N(R¹³)₂, SR¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, where R¹³ is selectedfrom the group consisting of hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₂-C₆ alkenyl, C₂-C₆ haloalkenyl, C₂-C₆ alkynyl, C₂-C₆ haloalkynyl,C₃-C₇ cycloalkyl,wherein R¹² is selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted haloalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl;R¹³ is selected from the group consisting of hydrogen, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ haloalkenyl, C₂-C₆ alkynyl, C₂-C₆haloalkynyl, C₃-C₇ cycloalkyl, C₁-C₆ alkyl substituted by OR¹³, C₁-C₆alkyl substituted by SR¹³, C₁-C₆ alkyl substituted by N(HR¹³), N(R¹³)₂,C₂-C₆ haloalkyl, COOR¹³, C(O)N(R¹³)₂, SO₂R¹³, COOR¹³, C₁-C₆ alkyl,C₂-C₆, alkenyl, C₂-C₆ haloalkenyl, C₂-C₆ alkynyl, C₂-C₆ haloalkynyl,C₃-C₇ cycloalkyl, and a 3- to 7-membered heterocyclic ring including 1to 2 ring members selected from the group consisting of O, S, N, andN(R¹³), wherein said C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆haloalkenyl, C₂-C₆ alkynyl, C₂-C₆ haloalkynyl, C₃-C₇ cycloalkyl, and 3-to 7-membered heterocyclic ring groups are optionally substituted by oneor more substituents independently selected from the group consisting ofCN, OR¹³, N(R¹³)₂, and SR¹³, and wherein said C₃-C₇ cycloalkyl and 3- to7-membered heterocyclic ring are each further optionally substitutedwith a member of the group consisting of C₁-C₃ alkyl and C₁-C₃haloalkyl, halogen, CN, OR¹³, N(R¹³)₂, COOR¹³, C(O)N(R¹³)₂, SR¹³,SO₂R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ haloalkenyl,C₂-C₆ alkynyl, C₂-C₆ haloalkynyl, C₃-C₆ cycloalkyl, and a 3- to6-membered heterocyclic ring including 1 to 2 ring members selected fromthe group consisting of O, S, N, and N(R¹³), wherein said C₁-C₆ alkyl,C₂-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ haloalkenyl;Q is selected from hydrogen, C₁-C₂₀ alkyl, C₁-C₂₀ haloalkyl, C₂-C₂₀alkenyl, C₂-C₂₀ haloalkenyl, C₂-C₂₀ alkynyl, C₂-C₂₀ haloalkynyl, C₃-C₇cycloalkyl, and a 3- to 7-membered heterocyclic ring including 1 to 2ring members selected from the group consisting of O, S, N, and N(R¹⁰),wherein said C₁-C₂₀ alkyl, C₂-C₂₀ haloalkyl, C₂-C₆ alkenyl, C₂-C₂₀haloalkenyl, C₃-C₇ cycloalkyl, and 3- to 7-membered heterocyclic ringgroups are optionally substituted by one or more substituentsindependently selected from the group consisting of CN, OR¹⁰, N(R¹⁰)₂,and SR¹⁰, and wherein said C₃-C₇cycloalkyl and 3- to 7-memberedheterocyclic ring are each further optionally substituted with a memberof the group consisting of C₁-C₃ alkyl and C₁-C₃ haloalkyl;wherein R⁹ and R¹⁰ are independently defined as above; andwherein R¹² and R¹³ are independently defined as above;

In one embodiment, the compounds of general formula (Ia), andpharmaceutically acceptable salts of the foregoing, the compounds areisotopically enriched with deuterium. In aspects of these embodiments,one or more of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, R¹² and R¹³ mayinclude deuterium;

In an embodiment, the present application includes a compound of Formula(ID), (1E) and (IF) or a pharmaceutically acceptable salt, solvate orprodrug thereof:

R³ to R⁶ are independently selected from the group consisting ofhydrogen and deuterium;R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl, whereinR⁷ and R⁸ may be taken together with the atoms to which they areattached form a 3- or 7-membered cyclic or heterocyclic ring; R¹⁰ isselected from the group consisting of hydrogen, halogen, cyano and loweralkyl;Q′ is selected from the group consisting of:

In an embodiment, the application includes a compound of Formula (IB)and Formula (1C) or a pharmaceutically acceptable salt, solvate orprodrug thereof:

wherein R¹ is selected from the group consisting of hydrogen, C₁-C₃alkyl, —(CH₂)P(O)(OR¹²); CO(R¹²), COO(R¹²), C(O)N(R¹²)₂, SO(R¹²) andSO₂(R¹²);R² to R⁶ are independently selected from the group consisting ofhydrogen and lower alkyl;R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl, whereinR⁷ and R⁸ may be taken together with the atoms to which they areattached form a 3- or 7-membered cyclic or heterocyclic ring;R¹⁰ is selected from the group consisting of hydrogen, halogen, cyanoand lower alkyl;wherein R¹² is selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted haloalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl;R¹³ is selected from the group consisting of hydrogen, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ haloalkenyl, C₂-C₆ alkynyl, C₂-C₆haloalkynyl, C₃-C₇ cycloalkyl, C₁-C₆ alkyl substituted by OR¹³, C₁-C₆alkyl substituted by SR¹³, C₁-C₆ alkyl substituted by N(HR¹³), N(R¹³)₂,C₂-C₆ haloalkyl, COOR¹³, C(O)N(R¹³)₂, SO₂R¹³, COOR¹³, C₁-C₆ alkyl,C₂-C₆, alkenyl, C₂-C₆ haloalkenyl, C₂-C₆ alkynyl, C₂-C₆ haloalkynyl,C₃-C₇ cycloalkyl, and a 3- to 7-membered heterocyclic ring including 1to 2 ring members selected from the group consisting of O, S, N, andN(R¹³), wherein said C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆haloalkenyl, C₂-C₆ alkynyl, C₂-C₆ haloalkynyl, C₃-C₇ cycloalkyl, and 3-to 7-membered heterocyclic ring groups are optionally substituted by oneor more substituents independently selected from the group consisting ofCN, OR¹³, N(R¹³)₂, and SR¹³, and wherein said C₃-C₇ cycloalkyl and 3- to7-membered heterocyclic ring are each further optionally substitutedwith a member of the group consisting of C₁-C₃ alkyl and C₁-C₃haloalkyl, halogen, CN, OR¹³, N(R¹³)₂, COOR¹³, C(O)N(R¹³)₂, SR¹³,SO₂R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ haloalkenyl,C₂-C₆ alkynyl, C₂-C₆ haloalkynyl, C₃-C₆ cycloalkyl, and a 3- to6-membered heterocyclic ring including 1 to 2 ring members selected fromthe group consisting of O, S, N, and N(R¹³), wherein said C₁-C₆ alkyl,C₂-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ haloalkenyl; andQ′ is selected from the group consisting of:

In an embodiment, the present application includes a compound of Formula(ID), (1E), (IF) and (IG) or a pharmaceutically acceptable salt, solvateor prodrug thereof:

R³ to R⁶ are independently selected from the group consisting ofhydrogen and deuterium;R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, deuterium, lower alkyl and lower deuterated alkyl;R¹⁰ is selected from the group consisting of hydrogen, halogen, cyanoand lower alkyl; andQ′ is selected from the groups defined above.In one embodiment, the compounds of general formula (I), andpharmaceutically acceptable salts of the foregoing, the compounds areisotopically enriched with deuterium. In aspects of these embodiments,one or more of R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R¹⁰ may include deuterium;

In one embodiment, the compounds of general formula (I), andpharmaceutically acceptable salts of the foregoing, the compounds areisotopically enriched with deuterium. In aspects of these embodiments,one or more of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³may include deuterium.

In one embodiment, the compounds of general formula (I), andpharmaceutically acceptable salts of the foregoing, the compounds areisotopically enriched with deuterium. In aspects of these embodiments,one or more of R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R¹⁰ may include deuterium.

In an embodiment, the compound of the present application is selectedfrom the compounds of Examples 1 to 42 as illustrated below or apharmaceutically acceptable salt, solvate and/or prodrug thereof:

TABLE 1 Representative compounds of compound of Formula (I). ChemicalCom- Formula/ pound Molecular ID # Chemical Structure IUPAC Name WeightI-1 

3-(2-(dimethyl- amino)ethyl)-6-fluoro- 1H-indol-4-yl di- hydrogenphosphate C12H16FN2O4P 302.24 I-2 

3-(2-(bis(methyl- d3)amino)ethyl)-1H- indol-4-yl dihydrogen phosphateC12H11D6N2O4P 290.29 I-3 

3-(2-(bis(methyl- d3)amino)ethyl- 1,1,2,2-d4)-1H-indol-4- yl dihydrogenphosphate C12H7D10N2O4P 294.31 I-4 

6-cyano-3-(2-((methyl- d3)amino)ethyl)-1H- indol-4-yl dihydrogenphosphate C12H11D3N3O4P 298.25 I-5 

3-(2-(bis(methyl- d3)amino)ethyl)-6- fluoro-1H-indol-4-yl dihydrogenphosphate C12H10D6FN2O4P 308.28 I-6 

3-(2-(bis(methyl- d3)amino)ethyl)-6- cyano-1H-indol-4-yl dihydrogenphosphate C13H10D6N3O4P 315.30 I-7 

(((3-(2- (dimethylamino)ethyl)- 1H-indol-4- yl)oxy)methyl) phosphonicacid C13H19N2O4P 298.28 I-8 

((3-(2- (dimethylamino)ethyl)- 4-(phosphonooxy)-1H- indol-1-yl)methyl)phosphonic acid C13H20N2O7P2 378.26 I-9 

3-(2-(bis(methyl- d6)amino)ethyl)- 1H-indol-4-yl dihydrogen phosphateC14H11D10N2O4P 322.37 I-10

((3-(2- (dimethylamino)ethyl)- 4-hydroxy-1H-indol-1-yl)methyl)phosphonic acid de C13H19N2O4P: 298.28 I-11

3-(2-(bis(methyl- d6)amino)ethyl)-6- fluoro- 1H-indol-4-yl dihydrogenphosphate C12H10D6FN2O4P 308.28 I-12

3-(2-(bis(methyl- d3)amino)ethyl)-6- cyano-1H-indol-4-yl dihydrogenphosphate C13H10D6N3O4P 315.30 I-13

((3-(2-(bis(methyl- d3)amino)ethyl)-4- (phosphonooxy)-1H- indol-1-yl)methyl)phosphonic acid C13H14D6N2O7P2 384.29 I-14

(1-((3-(2- (dimethylamino)ethyl)- 1H-indol-4- yl)oxy)ethyl) phosphonicacid C14H21N2O4P 312.31 I-15

(1-((3-(2-(bis(methyl- d3)amino)ethyl)-1H- indol-4- yl)oxy)ethyl)phosphonic acid C14H15D6N2O4P 318.34 I-16

3-(2-(bis(methyl- d3)amino)ethyl)-1H- indol-4-yl glycinate C14H13D6N3O2267.36 I-17

3-(2-(bis(methyl- d3)amino)ethyl)-1H- indol-4-yl D-alaninateC15H15D6N3O2 281.39 I-18

(Z)-4-((3-(2- (bis(methyl- d3)amino)ethyl)-1H- indol-4-yl)oxy)-4-oxobut-2-enoic acid C16H12D6N2O4 308.37 I-19

(E)-4-((3-(2- (bis(methyl- d3)amino)ethyl)-1H- indol-4-yl)oxy)-4-oxobut-2-enoic acid C16H12D6N2O4 308.37 I-20

4-((3-(2-(bis(methyl- d3)amino)ethyl)-1H- indol-4-yl)oxy)-4- oxobutanoicacid C16H14D6N2O4 310.38 I-21

3-(2-(bis(methyl- d3)amino)ethyl)-1H- indol-4-yl acetate C14H12D6N2O2252.35 I-22

3 3-(2-(bis(methyl- d3)amino)ethyl- 1,1,2,2-d4)-1H-indol-4- yl acetateC14H8D10N2O2 256.37 I-23

((4-acetoxy-3-(2- (bis(methyl- d3)amino)ethyl)-1H- indol-1-yl)methyl)phosphonic acid C15H15D6N2O5P 346.35 1-24

3-(2- (dimethylamino)ethyl)- 1H-indol-4-yl (9Z,12Z)- octadeca-9,12-dienoate C30H46N2O2 466.71 1-25

3-(2-(d6- dimethylamino)ethyl)- 1H-indol-4-yl (9Z,12Z)- octadeca-9,12-dienoate-11,11-d2 C30H38D8N2O2: 474.76 1-26

3-(2- (dimethylamino)ethyl)- 1H-indol-4-yl (9Z,12Z)- octadeca-9,12-dienoate-11,11-d2 C30H44D2N2O2 468.72 1-27

3-(2-(bis(methyl- d3)amino)ethyl)-1H- indol-4-yl (9Z,12Z)-octadeca-9,12- dienoate C30H40D6N2O2 472.75 1-28

3-(2-(bis(methyl- d3)amino)ethyl- 1,1,2,2-d4)-1H-indol-4- yl(9Z,12Z)-octadeca- 9,12-dienoate C30H36D10N2O2 476.77 I-29

3-(2-(bis(methyl- d6)amino)ethyl- 1,1,2,2-d4)-1H-indol-4- yl(9Z,12Z)-octadeca- 9,12-dienoate-11,11- d2 C30H34D12N2O2: 478.78 I-30

3-(2-(d10- diethylamino)ethyl-d4)- 1H-indol-4-yl (9Z,12Z)-octadeca-9,12- dienoate C32H36D14N2O2 508.85 1-31

3-(2-(d10- diethylamino)ethyl-d4)- 1H-indol-4-yl (9Z,12Z)-octadeca-9,12- dienoate-11,11-d2 C32H34D16N2O2 510.86 1-32

3-(2- (diethylamino)ethyl- d4)-1H-indol-4-yl (9Z,12Z)-octadeca-9,12-dienoate C32H46D4N2O2 498.79 1-33

3-(2- (diethylamino)ethyl- d4)-1H-indol-4-yl (9Z,12Z)-octadeca-9,12-dienoate-11,11- d2 C32H44D6N2O2 500.80 1-34

3-(2-(pyrrolidin-1- yl)ethyl-1,1,2,2-d4)- 1H-indol-4-yl (9Z,12Z)-octadeca-9,12- dienoate C32H44D4N2O2 Exact Mass: 496.40 MolecularWeight: 496.77 1-35

3-(2-(pyrrolidin-1- yl)ethyl-1,1,2,2-d4)- 1H-indol-4-yl (9Z,12Z)-octadeca-9,12- dienoate-11,11-d2 C32H42D6N2O2 498.78 1-36

3-(2- (dimethylamino)ethyl)- 1H-indol-4-yl (S)-3- (aminomethyl)-5-methylhexanoate C20H31N3O2 345.49 1-37

3-(2-(bis(methyl- d3)amino)ethyl)-1H- indol-4-yl (S)-3- (aminomethyl)-5-methylhexanoate C20H25D6N3O2 351.52 1-38

3-(2-(bis(methyl- d3)amino)ethyl- 1,1,2,2-d4)-1H-indol-4- yl(S)-3-(aminomethyl)- 5-methylhexanoate C20H21D10N3O2 355.55 1-39

3-(2- (dimethylamino)ethyl)- 1H-indol-4-yl 2-(1- (aminomethyl)cyclohexyl)acetate C21H31N3O2 357.50 1-40

3-(2-(bis(methyl- d3)amino)ethyl)-1H- indol-4-yl 2-(1- (aminomethyl)cyclohexyl)acetate C21H25D6N3O2 363.53 1-41

3-(2-(bis(methyl- d3)amino)ethyl)-1H- indol-4-yl [1,4′-bipiperidine]-1′- carboxylate C23H28D6N4O2 404.59 1-42

3-(2-(bis(methyl- d3)amino)ethyl)-1H- indol-4-yl dimethylcarbamateC15H15D6N3O2 281.39

Compounds that may be used in the compositions and methods describedherein include any compound having the structure of Formula (I):

or pharmaceutically acceptable salts thereof, as described herein. Usesof compounds of general formula (I) and processes for making compoundsof general formula (I) are also disclosed.

Exemplary acid addition salts include acetates, ascorbates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, lactates, maleates, methanesulfonates(“mesylates”), naphthalenesulfonates, nitrates, oxalates, phosphates,propionates, salicylates, succinates, sulfates, tartarates,thiocyanates, toluenesulfonates (also known as tosylates) and the like.Suitable salts include acid addition salts that may, for example, beformed by mixing a solution of a compound with a solution of apharmaceutically acceptable acid such as hydrochloric acid, sulfuricacid, acetic acid, trifluoroacetic acid, or benzoic acid. Additionally,acids that are generally considered suitable for the formation ofpharmaceutically useful salts from basic pharmaceutical compounds arediscussed, for example, by P. Stahl et al, Camille G. (eds.), andHandbook of Pharmaceutical Salts. Properties, Selection and Use. (2002)Zurich: Wiley VCH; S. Berge et al, Journal of Pharmaceutical Sciences1977 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al, The Practice of Medicinal Chemistry (1996),Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website). These disclosuresare incorporated herein by reference thereto.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamine, abutyl amine, choline, andsalts with amino acids such as arginine, lysine and the like. Basicnitrogen containing groups may be quartemized with agents such as loweralkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g., decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g., benzyl andphenethyl bromides), and others. Compounds carrying an acidic moiety canbe mixed with suitable pharmaceutically acceptable salts to provide, forexample, alkali metal salts (e.g., sodium or potassium salts), alkalineearth metal salts (e.g., calcium or magnesium salts), and salts formedwith suitable organic ligands such as quaternary ammonium salts. Also,in the case of an acid (—COOH) or alcohol group being present,pharmaceutically acceptable esters can be employed to modify thesolubility or hydrolysis characteristics of the compound.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention. In addition, when a compound ofthe invention contains both a basic moiety, such as, but not limited toan aliphatic primary, secondary, tertiary or cyclic amine, an aromaticor heteroaryl amine, pyridine or imidazole, and an acidic moiety, suchas, but not limited to tetrazole or carboxylic acid, zwitterions (“innersalts”) may be formed and are included within the terms “salt(s)” asused herein. It is understood that certain compounds of the inventionmay exist in zwitterionic form, having both anionic and cationic centerswithin the same compound and a net neutral charge. Such zwitterions areincluded within the invention.

In some embodiments, the compounds of the present application can alsoinclude tautomeric forms, such as keto-enol tautomers and the like.Tautomeric forms can be in equilibrium or sterically locked into oneform by appropriate substitution. It is intended that any tautomericforms which the compounds form, as well as mixtures thereof, areincluded within the scope of the present application.

The compounds of the present application may further exist in varyingpolymorphic forms and it is contemplated that any polymorphs, ormixtures thereof, which form are included within the scope of thepresent application.

The compounds of the present application may further be radiolabeled andaccordingly all radiolabeled versions of the compounds of theapplication are included within the scope of the present application.The compounds of the application also include those in which one or moreradioactive atoms are incorporated within their structure.

III. Compositions

The compounds of the present application are suitably formulated in aconventional manner into compositions using one or more carriers.Accordingly, the present application also includes a compositioncomprising one or more compounds of the application and a carrier. Thecompounds of the application are suitably formulated into pharmaceuticalcompositions for administration to subjects in a biologically compatibleform suitable for administration in vivo. Accordingly, the presentapplication further includes a pharmaceutical composition comprising oneor more compounds of the application and a pharmaceutically acceptablecarrier. In embodiments of the application the pharmaceuticalcompositions are used in the treatment of any of the diseases, disordersor conditions described herein.

The compounds of the application are administered to a subject in avariety of forms depending on the selected route of administration, aswill be understood by those skilled in the art. For example, a compoundof the application is administered by oral, inhalation, parenteral,buccal, sublingual, insufflation, epidurally, nasal, rectal, vaginal,patch, pump, minipump, topical or transdermal administration and thepharmaceutical compositions formulated accordingly. In some embodiments,administration is by means of a pump for periodic or continuousdelivery. Conventional procedures and ingredients for the selection andpreparation of suitable compositions are described, for example, inRemington's Pharmaceutical Sciences (2000-20th edition) and in TheUnited States Pharmacopeia: The National Formulary (USP 24 NF19)published in 1999.

Parenteral administration includes systemic delivery routes other thanthe gastrointestinal (GI) tract and includes, for example intravenous,intra-arterial, intraperitoneal, subcutaneous, intramuscular,transepithelial, nasal, intrapulmonary (for example, by use of anaerosol), intrathecal, rectal and topical (including the use of a patchor other transdermal delivery device) modes of administration.Parenteral administration may be by continuous infusion over a selectedperiod of time.

In some embodiments, a compound of the application is orallyadministered, for example, with an inert diluent or with an assimilableedible carrier, or it is enclosed in hard or soft shell gelatincapsules, or it is compressed into tablets, or it is incorporateddirectly with the food of the diet. In some embodiments, the compound isincorporated with excipient and used in the form of ingestible tablets,buccal tablets, troches, capsules, caplets, pellets, granules, lozenges,chewing gum, powders, syrups, elixirs, wafers, aqueous solutions andsuspensions and the like. In the case of tablets, carriers that are usedinclude lactose, corn starch, sodium citrate and salts of phosphoricacid. Pharmaceutically acceptable excipients include binding agents(e.g., pregelatinized maize starch, polyvinylpyrrolidone orhydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystallinecellulose or calcium phosphate); lubricants (e.g., magnesium stearate,talc or silica); disintegrants (e.g., potato starch or sodium starchglycolate); or wetting agents (e.g., sodium lauryl sulphate), orsolvents (e.g. medium chain triglycerides, ethanol, water). Inembodiments, the tablets are coated by methods well known in the art. Inthe case of tablets, capsules, caplets, pellets or granules for oraladministration, pH sensitive enteric coatings, such as Eudragits™designed to control the release of active ingredients are optionallyused. Oral dosage forms also include modified release, for exampleimmediate release and timed-release, formulations. Examples ofmodified-release formulations include, for example, sustained-release(SR), extended-release (ER, XR, or XL), time-release or timed-release,controlled-release (CR), or continuous-release (CR or Contin), employed,for example, in the form of a coated tablet, an osmotic delivery device,a coated capsule, a microencapsulated microsphere, an agglomeratedparticle, e.g., as of molecular sieving type particles, or, a finehollow permeable fiber bundle, or chopped hollow permeable fibers,agglomerated or held in a fibrous packet. Timed-release compositions areformulated, for example as liposomes or those wherein the activecompound is protected with differentially degradable coatings, such asby microencapsulation, multiple coatings, etc. Liposome delivery systemsinclude, for example, small unilamellar vesicles, large unilamellarvesicles and multilamellar vesicles. In some embodiments, liposomes areformed from a variety of phospholipids, such as cholesterol,stearylamine or phosphatidylcholines. For oral administration in acapsule form, useful carriers, solvents or diluents include lactose,medium chain triglycerides, ethanol and dried corn starch.

In some embodiments, liquid preparations for oral administration takethe form of, for example, solutions, syrups or suspensions, or they aresuitably presented as a dry product for constitution with water or othersuitable vehicle before use. When aqueous suspensions and/or emulsionsare administered orally, the compound of the application is suitablysuspended or dissolved in an oily phase that is combined withemulsifying and/or suspending agents. If desired, certain sweeteningand/or flavoring and/or coloring agents are added. Such liquidpreparations for oral administration are prepared by conventional meanswith pharmaceutically acceptable additives such as suspending agents(e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats);emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles(e.g., medium chain triglycerides, almond oil, oily esters or ethylalcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoatesor sorbic acid). Useful diluents include lactose and high molecularweight polyethylene glycols.

It is also possible to freeze-dry the compounds of the application anduse the lyophilizates obtained, for example, for the preparation ofproducts for injection.

In some embodiments, a compound of the application is administeredparenterally. For example, solutions of a compound of the applicationare prepared in water suitably mixed with a surfactant such ashydroxypropylcellulose. In some embodiments, dispersions are prepared inglycerol, liquid polyethylene glycols, DMSO and mixtures thereof with orwithout alcohol and in oils. Under ordinary conditions of storage anduse, these preparations contain a preservative to prevent the growth ofmicroorganisms. A person skilled in the art would know how to preparesuitable formulations. For parenteral administration, sterile solutionsof the compounds of the application are usually prepared and the pH's ofthe solutions are suitably adjusted and buffered. For intravenous use,the total concentration of solutes should be controlled to render thepreparation isotonic. For ocular administration, ointments or droppableliquids are delivered, for example, by ocular delivery systems known tothe art such as applicators or eye droppers. In some embodiments, suchcompositions include mucomimetics such as hyaluronic acid, chondroitinsulfate, hydroxypropyl methylcellulose or polyvinyl alcohol,preservatives such as sorbic acid, EDTA or benzyl chromium chloride andthe usual quantities of diluents or carriers. For pulmonaryadministration, diluents or carriers will be selected to be appropriateto allow the formation of an aerosol.

In some embodiments, a compound of the application is formulated forparenteral administration by injection, including using conventionalcatheterization techniques or infusion. Formulations for injection are,for example, presented in unit dosage form, e.g., in ampoules or inmulti-dose containers, with an added preservative. In some embodiments,the compositions take such forms as sterile suspensions, solutions oremulsions in oily or aqueous vehicles and contain formulating agentssuch as suspending, stabilizing and/or dispersing agents. In all cases,the form must be sterile and must be fluid to the extent that easysyringability exists. Alternatively, the compounds of the applicationare suitably in a sterile powder form for reconstitution with a suitablevehicle, e.g., sterile pyrogen-free water, before use.

In some embodiments, compositions for nasal administration areconveniently formulated as aerosols, drops, gels and powders. Forintranasal administration or administration by inhalation, the compoundsof the application are conveniently delivered in the form of a solution,dry powder formulation or suspension from a pump spray container that issqueezed or pumped by the patient or as an aerosol spray presentationfrom a pressurized container or a nebulizer. Aerosol formulationstypically comprise a solution or fine suspension of the active substancein a physiologically acceptable aqueous or non-aqueous solvent and areusually presented in single or multidose quantities in sterile form in asealed container, which, for example, take the form of a cartridge orrefill for use with an atomising device. Alternatively, the sealedcontainer is a unitary dispensing device such as a single dose nasalinhaler or an aerosol dispenser fitted with a metering valve which isintended for disposal after use. Where the dosage form comprises anaerosol dispenser, it will contain a propellant which is, for example, acompressed gas such as compressed air or an organic propellant such asfluorochlorohydrocarbon. Suitable propellants include but are notlimited to dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, heptafluoroalkanes, carbon dioxide or anothersuitable gas. In the case of a pressurized aerosol, the dosage unit issuitably determined by providing a valve to deliver a metered amount. Insome embodiments, the pressurized container or nebulizer contains asolution or suspension of the active compound. Capsules and cartridges(made, for example, from gelatin) for use in an inhaler or insufflatorare, for example, formulated containing a powder mix of a compound ofthe application and a suitable powder base such as lactose or starch.The aerosol dosage forms can also take the form of a pump-atomizer.

Compositions suitable for buccal or sublingual administration includetablets, lozenges and pastilles, wherein a compound of the applicationis formulated with a carrier such as sugar, acacia, tragacanth, orgelatin and glycerine. Compositions for rectal administration areconveniently in the form of suppositories containing a conventionalsuppository base such as cocoa butter.

Suppository forms of the compounds of the application are useful forvaginal, urethral and rectal administrations. Such suppositories willgenerally be constructed of a mixture of substances that is solid atroom temperature but melts at body temperature. The substances commonlyused to create such vehicles include but are not limited to theobromaoil (also known as cocoa butter), glycerinated gelatin, otherglycerides, hydrogenated vegetable oils, mixtures of polyethyleneglycols of various molecular weights and fatty acid esters ofpolyethylene glycol. See, for example: Remington's PharmaceuticalSciences, 16th Ed., Mack Publishing, Easton, Pa., 1980, pp. 1530-1533for further discussion of suppository dosage forms.

In some embodiments a compound of the application is coupled withsoluble polymers as targetable drug carriers. Such polymers include, forexample, polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxy-ethylaspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, in some embodiments, acompound of the application is coupled to a class of biodegradablepolymers useful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcrosslinked or amphipathic block copolymers of hydrogels.

A compound of the application including pharmaceutically acceptablesalts, solvates and/or prodrugs thereof is suitably used on their ownbut will generally be administered in the form of a pharmaceuticalcomposition in which the one or more compounds of the application (theactive ingredient) is in association with a pharmaceutically acceptablecarrier. Depending on the mode of administration, the pharmaceuticalcomposition will comprise from about 0.05 wt % to about 99 wt % or about0.10 wt % to about 70 wt %, of the active ingredient and from about 1 wt% to about 99.95 wt % or about 30 wt % to about 99.90 wt % of apharmaceutically acceptable carrier, all percentages by weight beingbased on the total composition.

In an embodiment of the application, compositions are formulated fororal administration and the one or more compounds are suitably in theform of tablets containing 0.1, 0.25, 0.5, 0.75, 1.0, 5.0, 10.0, 20.0,25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 75.0, 80.0, 90.0, 100.0, 150, 200,250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900,950 or 1000 mg of active ingredient per tablet.

In the above, the term “a compound” also includes embodiments whereinone or more compounds are referenced.

In some embodiments, the compounds of the application includingpharmaceutically acceptable salts, solvates and/or prodrugs thereof areused are administered in a composition comprising an additionaltherapeutic agent. Therefore the present application also includes apharmaceutical composition comprising one of more compounds of theapplication, or pharmaceutically acceptable salts, solvates and/orprodrugs thereof and an additional therapeutic agent, and optionally oneor more pharmaceutically acceptable excipients. In some embodiments, theadditional therapeutic agent is another known agent useful for treatmentof a disease, disorder or condition by activation of a serotoninreceptor, for example those listed in the Methods and Uses sectionbelow. In some embodiments, the additional therapeutic agent is apsychoactive drug.

In the above, the term “a compound” also includes embodiments whereinone or more compounds are referenced.

IV. Methods and Uses of the Application

The compounds of the application are serotonergic binding agents thatact as agonists or partial agonists at a serotonin receptor.

Accordingly, the present application includes a method for activating aserotonin receptor in a cell, either in a biological sample or in apatient, comprising administering an effective amount of one or morecompounds of the application to the cell. The application also includesa use of one or more compounds of the application for activating aserotonin receptor in a cell as well as a use of one or more compoundsof the application for the preparation of a medicament for activating aserotonin receptor in a cell. The application further includes one ormore compounds of the application for use in activating a serotoninreceptor in a cell.

As the compounds of the application are capable of activating aserotonin receptor, the compounds of the application are useful fortreating diseases, disorders or conditions by activating a serotoninreceptor. Therefore, the compounds of the present application are usefulas medicaments. Accordingly, the application also includes a compound ofthe application for use as a medicament.

The present application also includes a method of treating a disease,disorder or condition by activation of a serotonin receptor comprisingadministering a therapeutically effective amount of one or morecompounds of the application to a subject in need thereof.

The present application also includes a use of one or more compounds ofthe application for treatment of a disease, disorder or condition byactivation of a serotonin receptor as well as a use of one or morecompounds of the application for the preparation of a medicament fortreatment of a disease, disorder or condition by activation of aserotonin receptor. The application further includes one or morecompounds of the application for use in treating a disease, disorder orcondition by activation of a serotonin receptor.

In some embodiments, the serotonin receptor is 5-HT_(2A). Accordingly,the present application includes a method for activating 5-HT_(2A) in acell, either in a biological sample or in a patient, comprisingadministering an effective amount of one or more compounds of theapplication to the cell. The application also includes a use of one ormore compounds of the application for activating 5-HT_(2A) in a cell aswell as a use of one or more compounds of the application for thepreparation of a medicament for activating 5-HT_(2A) in a cell. Theapplication further includes one or more compounds of the applicationfor use in activating 5-HT_(2A) in a cell.

The present application also includes a method of treating a disease,disorder or condition by activation of 5-HT_(2A) comprisingadministering a therapeutically effective amount of one or morecompounds of the application to a subject in need thereof. The presentapplication also includes a use of one or more compounds of theapplication for treatment of a disease, disorder or condition byactivation of 5-HT_(2A) as well as a use of one or more compounds of theapplication for the preparation of a medicament for treatment of adisease, disorder or condition by activation of 5-HT_(2A). Theapplication further includes one or more compounds of the applicationfor use in treating a disease, disorder or condition by activation of5-HT_(2A).

In some embodiments, the compounds of the application are useful forpreventing, treating and/or reducing the severity of a mental illnessdisorder and/or condition in a subject. Therefore, in some embodiments,the disease, disorder or condition that is treated by activation of aserotonin receptor is a mental illness. Accordingly, the presentapplication also includes a method of treating a mental illnesscomprising administering a therapeutically effective amount of one ormore compounds of the application to a subject in need thereof. Thepresent application also includes a use of one or more compounds of theapplication for treatment a mental illness, as well as a use of one ormore compounds of the application for the preparation of a medicamentfor treatment of a mental illness. The application further includes oneor more compounds of the application for use in treating a mentalillness.

In some embodiments, the mental illness is selected from anxietydisorders such as generalized anxiety disorder, panic disorder, socialanxiety disorder and specific phobias; depression such as, hopelessness,loss of pleasure, fatigue and suicidal thoughts; mood disorders, such asdepression, bipolar disorder, cancer-related depression, anxiety andcyclothymic disorder; psychotic disorders, such as hallucinations,delusions, schizophrenia; impulse control and addiction disorders, suchas pyromania (starting fires), kleptomania (stealing) and compulsivegambling; alcohol addiction; drug addiction, such as opioid addiction;personality disorders, such as antisocial personality disorder,obsessive-compulsive personality disorder and paranoid personalitydisorder; obsessive-compulsive disorder (OCD), such as thoughts or fearsthat cause a subject to perform certain rituals or routines;post-traumatic stress disorder (PTSD); stress response syndromes(formerly called adjustment disorders); dissociative disorders, formerlycalled multiple personality disorder, or “split personality,” anddepersonalization disorder; factitious disorders; sexual and genderdisorders, such as sexual dysfunction, gender identity disorder and theparaphilia's; somatic symptom disorders, formerly known as apsychosomatic disorder or somatoform disorder; and combinations thereof.

In some embodiments, the disease, disorder or condition that is treatedby activation of a serotonin receptor comprises cognitive impairment;ischemia including stroke; neurodegeneration; refractory substance usedisorders; sleep disorders; pain, such as social pain, acute pain,cancer pain, chronic pain, breakthrough pain, bone pain, soft tissuepain, nerve pain, referred pain, phantom pain, neuropathic pain, clusterheadaches and migraine; obesity and eating disorders; epilepsies andseizure disorders; neuronal cell death; excitotoxic cell death; or acombination thereof.

In some embodiments, the mental illness is selected from hallucinationsand delusions and a combination thereof.

In some embodiments, the hallucinations are selected from visualhallucinations, auditory hallucinations, olfactory hallucinations,gustatory hallucinations, tactile hallucinations, proprioceptivehallucinations, equilibrioceptive hallucinations, nociceptivehallucinations, thermoceptive hallucinations and chronoceptivehallucinations, and a combination thereof.

In some embodiments, the disease, disorder or condition that is treatedby activation of a serotonin receptor is psychosis or psychoticsymptoms. Accordingly, the present application also includes a method oftreating psychosis or psychotic symptoms comprising administering atherapeutically effective amount of one or more compounds of theapplication to a subject in need thereof.

The present application also includes a use of one or more compounds ofthe application for treatment of psychosis or psychotic symptoms, aswell as a use of one or more compounds of the application for thepreparation of a medicament for treatment of psychosis or psychoticsymptoms. The application further includes one or more compounds of theapplication for use in treating psychosis or psychotic symptoms.

In some embodiments, administering to said subject in need thereof atherapeutically effective amount of the compounds of the applicationdoes not result in a worsening of psychosis or psychotic symptoms suchas, but not limited to, hallucinations and delusions. In someembodiments, administering to said subject in need thereof atherapeutically effective amount of the compounds of the applicationresults in an improvement of psychosis or psychotic symptoms such as,but not limited to, hallucinations and delusions. In some embodiments,administering to said subject in need thereof a therapeuticallyeffective amount of the compounds of the application results in animprovement of psychosis or psychotic symptoms.

In some embodiments, the compounds of the application are useful fortreating a central nervous system (CNS) disease, disorder or conditionand/or a neurological disease, disorder or condition in a subject inneed of therapy, comprising administering a therapeutically effectiveamount of a compound of general formula (I), or a pharmaceuticallyacceptable salt thereof to the subject.

Therefore, in some embodiments, the disease, disorder or condition thatis treated by activation of a serotonin receptor is a central nervoussystem (CNS) disease, disorder or condition and/or a neurologicaldisease, disorder or condition. Accordingly, the present applicationalso includes a method of treating a CNS disease, disorder or conditionand/or a neurological disease, disorder or condition comprisingadministering a therapeutically effective amount of one or morecompounds of the application to a subject in need thereof. The presentapplication also includes a use of one or more compounds of theapplication for treatment a CNS disease, disorder or condition and/or aneurological disease, disorder or condition, as well as a use of one ormore compounds of the application for the preparation of a medicamentfor treatment of a CNS disease, disorder or condition and/or aneurological disease, disorder or condition. The application furtherincludes one or more compounds of the application for use in treating aCNS disease, disorder or condition and/or a neurological disease,disorder or condition.

In some embodiments the CNS disease, disorder or condition and/orneurological disease, disorder or condition is selected fromneurological diseases including neurodevelopmental diseases andneurodegenerative diseases such as Alzheimer's disease; preseniledementia; senile dementia; vascular dementia; Lewy body dementia;cognitive impairment, Parkinson's disease and Parkinsonian relateddisorders such as Parkinson dementia, corticobasal degeneration, andsupranuclear palsy; epilepsy; CNS trauma; CNS infections; CNSinflammation; stroke; multiple sclerosis; Huntington's disease;mitochondrial disorders; Fragile X syndrome; Angelman syndrome;hereditary ataxias; neuro-ontological and eye movement disorders;neurodegenerative diseases of the retina amyotrophic lateral sclerosis;tardive dyskinesias; hyperkinetic disorders; attention deficithyperactivity disorder and attention deficit disorders; restless legsyndrome; Tourette's syndrome; schizophrenia; autism spectrum disorders;tuberous sclerosis; Rett syndrome; cerebral palsy; disorders of thereward system including eating disorders such as anorexia nervosa (“AN”)and bulimia nervosa (“BN”); and binge eating disorder (“BED”),trichotillomania, dermotillomania, nail biting; migraine; fibromyalgia;and peripheral neuropathy of any etiology, and combinations thereof.

In another embodiment, the compounds general formula (I) are directedtowards a method for preventing, treating, and/or reducing the severityof a mental illness disorder and/or condition in a subject. For example,the illness disorder comprises anxiety disorders include generalizedanxiety disorder, panic disorder, social anxiety disorder, and specificphobias; depression such as, hopelessness, loss of pleasure, fatigue,and suicidal thoughts; mood disorders, such as depression, bipolardisorder, cancer-related depression, anxiety, and cyclothymic disorder;psychotic disorders, such as hallucinations and delusions,schizophrenia; eating disorders e.g. anorexia nervosa, bulimia nervosa,and binge eating disorder; impulse control and addiction disorders e.g.Pyromania (starting fires), kleptomania (stealing), and compulsivegambling; alcohol addiction; drug addiction including opioid addiction;personality disorders include antisocial personality disorder,obsessive-compulsive personality disorder, and paranoid personalitydisorder; obsessive-compulsive disorder (OCD) e.g. thoughts or fearsthat cause them to perform certain rituals or routines; post-traumaticstress disorder (PTSD); stress response syndromes (formerly calledadjustment disorders); dissociative disorders, formerly called multiplepersonality disorder, or “split personality,” and depersonalizationdisorder are examples of dissociative disorders; factitious disorders;sexual and gender disorders e.g. sexual dysfunction, gender identitydisorder, and the paraphilia's; somatic symptom disorders, formerlyknown as a psychosomatic disorder or somatoform disorder; attentionaldisorders including attentional deficit disorder, attentional deficithyperactivity disorder and attentional deficits seen in other disordersincluded here; tic disorders: People with tic disorders such as,Tourette's syndrome; and other diseases or conditions, including varioussleep-related problems and many forms of dementia, including Alzheimer'sdisease, Lewy body dementia, Parkinson's disease dementia andfrontotemporal dementia. In embodiments, the condition comprisescognitive impairment, ischemia including stroke, neurodegeneration,refractory substance use disorders, sleep disorders, pain, e.g. surgicalpain, social pain, acute pain, cancer pain, chronic pain, breakthroughpain, bone pain, soft tissue pain, nerve pain, referred pain, phantompain, neuropathic pain, cluster headaches and migraine, obesity andeating disorders, epilepsies and seizure disorders, neuronal cell death,excitotoxic cell death, or a combination thereof.

In yet another embodiment relates to methods of treating a CNS disorderin a patient in need of therapy, comprising administering atherapeutically effective amount of a compound of general formula (I),or a pharmaceutically acceptable salt thereof to the patient. In aspectsof this embodiment, CNS disorder is, but not limited to mental illnessdisorders above;

In some embodiments, the subject is a mammal. In another embodiment, thesubject is human. In some embodiments, the subject is a non-humananimal. In some embodiments, the subject is canine. In some embodiments,the subject is feline. Accordingly, the compounds, methods and uses ofthe present application are directed to both human and veterinarydiseases, disorders and conditions.

In some embodiments, the compounds of the application are useful fortreating behavioral problems in subjects that are felines or canines.

Therefore, in some embodiments, the disease, disorder or condition thatis treated by activation of a serotonin receptor is behavioral problemsin subjects that are felines or canines. Accordingly, the presentapplication also includes a method of treating a behavioral problemcomprising administering a therapeutically effective amount of one ormore compounds of the application to a non-human subject in needthereof. The present application also includes a use of one or morecompounds of the application for treatment a behavioral problem in anon-human subject, as well as a use of one or more compounds of theapplication for the preparation of a medicament for treatment of abehavioral problem in a non-human subject. The application furtherincludes one or more compounds of the application for use in treating abehavioral problem in a non-human subject.

In some embodiments, the behavioral problems are selected from, but arenot limited to, anxiety, fear, stress, sleep disturbances, cognitivedysfunction, aggression, excessive noise making, scratching, biting anda combination thereof.

In some embodiments, the non-human subject is canine. In someembodiments, the non-human subject is feline.

The present application also includes a method of treating a disease,disorder or condition by activation of a serotonin receptor comprisingadministering a therapeutically effective amount of one or morecompounds of the application in combination with another known agentuseful for treatment of a disease, disorder or condition by activationof a serotonin receptor to a subject in need thereof. The presentapplication also includes a use of one or more compounds of theapplication in combination with another known agent useful for treatmentof a disease, disorder or condition by activation of a serotoninreceptor for treatment of a disease, disorder or condition by activationof a serotonin receptor, as well as a use of one or more compounds ofthe application in combination with another known agent useful fortreatment of a disease, disorder or condition by activation of aserotonin receptor for the preparation of a medicament for treatment ofa disease, disorder or condition by activation of a serotonin receptor.The application further includes one or more compounds of theapplication in combination with another known agent useful for treatmentof a disease, disorder or condition by activation of a serotoninreceptor for use in treating a disease, disorder or condition byactivation of a serotonin receptor.

In some embodiments, the disease, disorder or condition that is treatedby activation of a serotonin receptor is a mental illness. In someembodiments, the disease, disorder or condition that is treated byactivation of a serotonin receptor is a central nervous system (CNS)disease, disorder or condition and/or a neurological disease, disorderor condition. In some embodiments, the disease, disorder or conditionthat is treated by activation of a serotonin receptor is psychosis orpsychotic symptoms. In some embodiments, the disease, disorder orcondition that is treated by activation of a serotonin receptor isbehavioral problems in a non-human subject.

In some embodiments, the disease, disorder or condition that is treatedby activation of a serotonin receptor is a mental illness and the one ormore compounds of the application are administered in combination withone or more additional treatments for a mental illness. In someembodiments, the additional treatments for a mental illness is selectedfrom antipsychotics, including typical antipsychotics and atypicalantipsychotics; antidepressants including selective serotonin reuptakeinhibitors (SSRIs) and selective norepinephrine reuptake inhibitors(SNRIs), tricyclic antidepressants and monoamine oxidase inhibitors(MAOIs) (e.g. bupropion); anti-anxiety medication includingbenzodiazepines such as alprazolam; mood stabilizers such as lithium andanticonvulsants such carbamazepine, divalproex (valproic acid),lamotrigine, gabapentin and topiramate.

In some embodiments, the disease, disorder or condition that is treatedby activation of a serotonin receptor is selected from attention deficithyperactivity disorder and attention deficit disorder and a combinationthereof. In some embodiments, the disease, disorder or condition that istreated by activation of a serotonin receptor is attention deficithyperactivity disorder and/or attention deficit disorder and acombination thereof and the one or more compounds of the application areadministered in combination with one or more additional treatments forattention deficit hyperactivity disorder and/or attention deficitdisorder and a combination thereof. In some embodiments, the additionaltreatments for attention deficit hyperactivity disorder and/or attentiondeficit disorder and a combination thereof are selected frommethylphenidate, atomoxetine and amphetamine and a combination thereof.

In some embodiments, the disease, disorder or condition that is treatedby activation of a serotonin receptor is dementia or Alzheimer's diseaseand the one or more compounds of the application are administered incombination with one or more additional treatments for dementia orAlzheimer's disease. In some embodiments, the additional treatments fordementia and Alzheimer's disease are selected acetylcholinesteraseinhibitors, NMDA antagonists and muscarinic agonists and antagonists,and nicotinic agonists.

In some embodiments, the acetylcholinesterase inhibitors are selectedfrom donepezil, galantamine, rivastigmine, and phenserine, andcombinations thereof.

In some embodiments, the NMDA antagonists are selected from MK-801,ketamine, phencyclidine, and memantine, and combinations thereof.

In some embodiments, the nicotinic agonists is nicotine, nicotinic acid,nicotinic alpha7 agonists or alpha2 beta4 agonists or combinationsthereof.

In some embodiments, the muscarinic agonists is a muscarinic M1 agonistor a muscarinic M4 agonist, or combinations thereof.

In some embodiments, the muscarinic antagonist is a muscarinic M2antagonist.

In some embodiments, the disease, disorder or condition that is treatedby activation of a serotonin receptor is psychosis or psychotic symptomsand the one or more compounds of the application are administered incombination with one or more additional treatments for psychosis orpsychotic symptoms. In some embodiments, the additional treatments forpsychosis or psychotic symptom are selected typical antipsychotics andatypical antipsychotics.

In some embodiments, the typical antipsychotics are selected fromacepromazine, acetophenazine, benperidol, bromperidol, butaperazine,carfenazine, chlorproethazine, chlorpromazine, chlorprothixene,clopenthixol, cyamemazine, dixyrazine, droperidol, fluanisone,flupentixol, fluphenazine, fluspirilene, haloperidol, levomepromazine,lenperone, loxapine, mesoridazine, metitepine, molindone, moperone,oxypertine, oxyprotepine, penfluridol, perazine, periciazine,perphenazine, pimozide, pipamperone, piperacetazine, pipotiazine,prochlorperazine, promazine, prothipendyl, spiperone, sulforidazine,thiopropazate, thioproperazine, thioridazine, thiothixene, timiperone,trifluoperazine, trifluperidol, triflupromazine and zuclopenthixol andcombinations thereof.

In some embodiments, the atypical antipsychotics are selected fromamoxapine, amisulpride, aripiprazole, asenapine, blonanserin,brexpiprazole, cariprazine, carpipramine, clocapramine, clorotepine,clotiapine, clozapine, iloperidone, levosulpiride, lurasidone,melperone, mosapramine, nemonapride, olanzapine, paliperidone,perospirone, quetiapine, remoxipride, reserpine, risperidone,sertindole, sulpiride, sultopride, tiapride, veralipride, ziprasidoneand zotepine, and combinations thereof.

In some embodiments, the disease, disorder or condition that is treatedby activation of a serotonin receptor is a mental illness and the one ormore compounds of the application are administered in combination withone or more additional treatments for a mental illness. In someembodiments, the additional treatments for a mental illness is selectedtypical antipsychotics and atypical antipsychotics.

In some embodiments, effective amounts vary according to factors such asthe disease state, age, sex and/or weight of the subject or species. Insome embodiments, the amount of a given compound or compounds that willcorrespond to an effective amount will vary depending upon factors, suchas the given drug(s) or compound(s), the pharmaceutical formulation, theroute of administration, the type of condition, disease or disorder, theidentity of the subject being treated and the like, but can neverthelessbe routinely determined by one skilled in the art.

In some embodiment, the compounds of the application are administeredone, two, three or four times a year. In some embodiments, the compoundsof the application are administered at least once a week. However, inanother embodiment, the compounds are administered to the subject fromabout one time per two weeks, three weeks or one month. In anotherembodiment, the compounds are administered about one time per week toabout once daily. In another embodiment, the compounds are administered1, 2, 3, 4, 5 or 6 times daily. The length of the treatment perioddepends on a variety of factors, such as the severity of the disease,disorder or condition, the age of the subject, the concentration and/orthe activity of the compounds of the application and/or a combinationthereof. It will also be appreciated that the effective dosage of thecompound used for the treatment may increase or decrease over the courseof a particular treatment regime. Changes in dosage may result andbecome apparent by standard diagnostic assays known in the art. In someinstances, chronic administration is required. For example, thecompounds are administered to the subject in an amount and for durationsufficient to treat the subject.

In some embodiments, the compounds of the application are administeredat doses that are hallucinogenic or psychotomimetic and taken inconjunction with psychotherapy or therapy and may occur once, twice,three, or four times a year. However, in some embodiments, the compoundsare administered to the subject once daily, once every two days, onceevery 3 days, once a week, once every two weeks, once a month, onceevery two months, or once every three months at doses that are nothallucinogenic or psychotomimetic.

A compound of the application is either used alone or in combinationwith other known agents useful for treating diseases, disorders orconditions by activation of a serotonin receptor, such as the compoundsof the application. When used in combination with other known agentsuseful in treating diseases, disorders by activation of a serotoninreceptor, it is an embodiment that a compound of the application isadministered contemporaneously with those agents. As used herein,“contemporaneous administration” of two substances to a subject meansproviding each of the two substances so that they are both active in theindividual at the same time. The exact details of the administrationwill depend on the pharmacokinetics of the two substances in thepresence of each other and can include administering the two substanceswithin a few hours of each other, or even administering one substancewithin 24 hours of administration of the other, if the pharmacokineticsare suitable. Design of suitable dosing regimens is routine for oneskilled in the art. In particular embodiments, two substances will beadministered substantially simultaneously, i.e., within minutes of eachother, or in a single composition that contains both substances. It is afurther embodiment of the present application that a combination ofagents is administered to a subject in a non-contemporaneous fashion. Insome embodiments, a compound of the present application is administeredwith another therapeutic agent simultaneously or sequentially inseparate unit dosage forms or together in a single unit dosage form.Accordingly, the present application provides a single unit dosage formcomprising one or more compounds of the application, an additionaltherapeutic agent and a pharmaceutically acceptable carrier.

The dosage of a compound of the application varies depending on manyfactors such as the pharmacodynamic properties of the compound, the modeof administration, the age, health and weight of the recipient, thenature and extent of the symptoms, the frequency of the treatment andthe type of concurrent treatment, if any and the clearance rate of thecompound in the subject to be treated. One of skill in the art candetermine the appropriate dosage based on the above factors. In someembodiments, one or more compounds of the application are administeredinitially in a suitable dosage that is adjusted as required, dependingon the clinical response. Dosages will generally be selected to maintaina serum level of the one or more compounds of the application from about0.01 μg/cc to about 1000 μg/cc, or about 0.1 μg/cc to about 100 μg/cc.As a representative example, oral dosages of one or more compounds ofthe application will range between about 10 μg per day to about 1000 mgper day for an adult, suitably about 10 μg per day to about 500 mg perday, more suitably about 10 μg per day to about 200 mg per day. Forparenteral administration, a representative amount is from about 0.0001mg/kg to about 10 mg/kg, about 0.0001 mg/kg to about 1 mg/kg, about 0.01mg/kg to about 0.1 mg/kg or about 0.0001 mg/kg to about 0.01 mg/kg willbe administered. For oral administration, a representative amount isfrom about 0.001 μg/kg to about 10 mg/kg, about 0.1 μg/kg to about 10mg/kg, about 0.01 μg/kg to about 1 mg/kg or about 0.1 μg/kg to about 1mg/kg. For administration in suppository form, a representative amountis from about 0.1 mg/kg to about 10 mg/kg or about 0.1 mg/kg to about 1mg/kg. In some embodiments of the application, compositions areformulated for oral administration and the one or more compounds aresuitably in the form of tablets containing 0.1, 0.25, 0.5, 0.75, 1.0,5.0, 10.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 75.0, 80.0, 90.0,100.0, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750,800, 850, 900, 950 or 1000 mg of active ingredient (one or morecompounds of the application) per tablet. In some embodiments of theapplication the one or more compounds of the application areadministered in a single daily, weekly or monthly dose or the totaldaily dose is divided into two, three or four daily doses.

In some embodiments, the compounds of the application are used oradministered in an effective amount which comprises administration ofdoses or dosage regimens that are devoid of clinically meaningfulpsychedelic/psychotomimetic actions. In some embodiments, the compoundsof the application are used or administered in an effective amount whichcomprises administration of doses or dosage regimens that provideclinical effects similar to those exhibited by a human plasma psilocinCmax of 4 ng/mL or less and/or human 5-HT_(2A) human CNS receptoroccupancy of 40% or less or those exhibited by a human plasma psilocinCmax of 1 ng/mL or less and/or human 5-HT_(2A) human CNS receptoroccupancy of 30% or less. In some embodiments, the compounds of theapplication are used or administered in an effective amount whichcomprises administration of doses or dosage regimens that provideclinical effects similar to those exhibited by a human plasma psilocinTmax in excess of 60 minutes, in excess of 120 minutes or in excess of180 minutes.

V. Preparation of Compounds

Compounds of the present application can be prepared by varioussynthetic processes. The choice of particular structural features and/orsubstituents may influence the selection of one process over another.The selection of a particular process to prepare a given compound of theapplication is within the purview of the person of skill in the art.Some starting materials for preparing compounds of the presentapplication are available from commercial chemical sources or may beextracted from cells, plants, animals or fungi. Other startingmaterials, for example as described below, are readily prepared fromavailable precursors using straightforward transformations that are wellknown in the art. In the Schemes below showing some embodiments ofmethods of preparation of compounds of the application, all variablesare as defined in Formula (I), unless otherwise stated.

In some embodiments of the application, the compounds of the applicationare generally prepared according to the process illustrated in SchemesII-IV.

In some embodiments, the compounds of Formula (I) are prepared as shownin Scheme II. Therefore, ortho-iodoanilin compounds of Formula (A) arecoupled with suitable unsaturated precursors such as disubstitutedalkyne compound of Formula (B) in the presence of a catalyst, such as aPd catalyst, to provide a compound of Formula (I) through known methods,for example, using the Pd catalysis procedure found in Chem. Eur. J.2019, 25, 897-903.

In some embodiments, the compounds of Formula (I) are synthesizedaccording to Scheme Ill. Therefore, a substituted indole compound ofFormula (C) is coupled with a suitable amino compound of Formula (E) inthe present of suitable coupling reagents such as oxalyl chloride toprovide compounds of Formula (D). The compounds of Formula (D) arereduced with suitable reducing agents such as Al-based reducing agentsto provide the compounds of general Formula (I).

A person skilled in the art would appreciate that further manipulationof the substituent groups using known chemistry can be performed on theintermediates and final compounds in the Schemes above to providealternative compounds of the application.

Salts of compounds of the application may be formed by methods known tothose of ordinary skill in the art, for example, by reacting a compoundof the application with an amount of acid or base, such as an equivalentamount, in a medium such as one in which the salt precipitates or inaqueous medium followed by lyophilization.

The formation of solvates will vary depending on the compound and thesolvate. In general, solvates are formed by dissolving the compound inthe appropriate solvent and isolating the solvate by cooling or using anantisolvent. The solvate is typically dried or azeotroped under ambientconditions. The selection of suitable conditions to form a particularsolvate can be made by a person skilled in the art. Examples of suitablesolvents are ethanol, water and the like. When water is the solvent, themolecule is referred to as a “hydrate”. The formation of solvates of thecompounds of the application will vary depending on the compound and thesolvate. In general, solvates are formed by dissolving the compound inthe appropriate solvent and isolating the solvate by cooling or using anantisolvent. The solvate is typically dried or azeotroped under ambientconditions. The selection of suitable conditions to form a particularsolvate can be made by a person skilled in the art.

Isotopically-enriched compounds of the application and pharmaceuticallyacceptable salts, solvates and/or prodrug thereof, can be preparedwithout undue experimentation by conventional techniques well known tothose skilled in the art or by processes analogous to those described inthe Schemes and Examples herein using suitable isotopically-enrichedreagents and/or intermediates.

Throughout the processes described herein it is to be understood that,where appropriate, suitable protecting groups will be added to andsubsequently removed from, the various reactants and intermediates in amanner that will be readily understood by one skilled in the art.Conventional procedures for using such protecting groups as well asexamples of suitable protecting groups are described, for example, in“Protective Groups in Organic Synthesis”, T. W. Green, P. G. M. Wuts,Wiley-Interscience, New York, (1999). It is also to be understood that atransformation of a group or substituent into another group orsubstituent by chemical manipulation can be conducted on anyintermediate or final product on the synthetic path toward the finalproduct, in which the possible type of transformation is limited only byinherent incompatibility of other functionalities carried by themolecule at that stage to the conditions or reagents employed in thetransformation. Such inherent incompatibilities and ways to circumventthem by carrying out appropriate transformations and synthetic steps ina suitable order, will be readily understood to one skilled in the art.Examples of transformations are given herein and it is to be understoodthat the described transformations are not limited only to the genericgroups or substituents for which the transformations are exemplified.References and descriptions of other suitable transformations are givenin “Comprehensive Organic Transformations—A Guide to Functional GroupPreparations” R. C. Larock, VHC Publishers, Inc. (1989). References anddescriptions of other suitable reactions are described in textbooks oforganic chemistry, for example, “Advanced Organic Chemistry”, March, 4thed. McGraw Hill (1992) or, “Organic Synthesis”, Smith, McGraw Hill,(1994). Techniques for purification of intermediates and final productsinclude, for example, straight and reversed phase chromatography oncolumn or rotating plate, recrystallisation, distillation andliquid-liquid or solid-liquid extraction, which will be readilyunderstood by one skilled in the art.

EXAMPLES

The following non-limiting examples are illustrative of the presentapplication. General Methods

All starting materials used herein were commercially available orearlier described in the literature. The ¹H and ¹³C NMR spectra wererecorded either on Bruker 300, Bruker DPX400 or Varian +400spectrometers operating at 300, 400 and 400 MHz for ¹H NMR respectively,using TMS or the residual solvent signal as an internal reference, indeuterated chloroform as solvent unless otherwise indicated. Allreported chemical shifts are in ppm on the delta-scale, and the finesplitting of the signals as appearing in the recordings is generallyindicated, for example as s: singlet, br s: broad singlet, d: doublet,t: triplet, q: quartet, m: multiplet. Unless otherwise indicated, in thetables below, ¹H NMR data was obtained at 400 MHz, using CDCl₃ as thesolvent.

Purification of products was carried out using Chem Elut ExtractionColumns (Varian, cat #1219-8002), Mega BE-SI (Bond Elut Silica) SPEColumns (Varian, cat #12256018; 12256026; 12256034) or by flashchromatography in silica-filled glass columns.

The following compounds were prepared using one or more of the syntheticmethods outlined in Schemes I to IV.

A. Synthesis of Exemplary Compounds of the Application

Example 1:2-(4-fluoro-1H-indol-3-yl)-N,N-bis(methyl-d₃)ethan-1-amine-1,1,2,2-d₄(I-43)

Synthesis of 2-(4-fluoro-1H-indol-3-yl)-N,N-bis(methyl-d)-2-oxoacetamide(15)

A solution of 4-fluoro-1H-indole (1.0 g, 7.39 mmol) in dry ether (20 mL)was treated with oxalyl chloride (0.63 mL, 7.39 mmol) at 0° C. Thereaction was brought to room temperature and stirred for additional 16h. The reaction was cooled to 0° C., treated with bis(methyl-d₃)aminehydrochloride (1.62 g, 18.49 mmol, free based with K₂CO₃ in THF) over aperiod of 5 min. The reaction was brought to room temperature andstirred for 4 h. The reaction was quenched with water (50 mL) andproduct was extracted into ethyl acetate (2×75 mL). Combined ethylacetate layer was washed with brine (25 mL) and dried (Na₂SO₄). Solventwas evaporated and crude was purified by flash column chromatography(MeOH: CH₂Cl₂, 5:95) on silica gel to obtain the title compound 15 (0.49g, 27.6%) as an off-white solid. ¹H NMR (CDC₃): δ 10.71 (s, 1H), 7.72(d, 1H, J=3.0 Hz), 7.15-7.10 (m, 2H), 6.94-6.87 (m, 1H); ESI-MS (m/z,%): 263 (M+Na, 100).

Synthesis of2-(4-fluoro-1H-indol-3-yl)-N,N-bis(methyl-d₃)ethan-1-amine-1,1,2,2-d4(I-43)

A suspension of Lithium aluminum deuteride (0.19 g, 1.12 mmol) in dryTHF (5 mL) was treated with2-(4-fluoro-1H-indol-3-yl)-N,N-bis(methyl-d3)-2-oxoacetamide (0.27 g,1.33 mmol) in dry THF (10 mL) at 0° C. over a period of 10 min. Thereaction was brought to room temperature, then refluxed for additional16 hours, after work-up and column chromatography purification led tothe title compound 17 (0.1 g, 42%) as a pale yellow semi-solid. ¹H NMR(DMSO-d₆): δ 11.08 (s, 1H), 7.17-7.14 (m, 2H), 7.05-6.97 (m, 1H),6.75-6.67 (m, 1H); ESI-MS (m/z, %): 217 (MH*, 100).

Example 2:2-(4-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4(I-44)

In a similar manner as described for I-43, compound2-(4-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4was prepared from 2 g of 4-methoxy-1H-indole through2-(4-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)-2-oxoacetamide reductionwith Lithium aluminum deuteride to obtain the title compound (150 mg,71%) as a light weight solid.

Example 3 and Example 4

Example 3: Synthesis of3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (I-45)Synthesis of2-(4-(benzyloxy)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4(I-46)

Prepared from2-(4-(benzyloxy)-1H-indol-3-yl)-N,N-bis(methyl-d3)-2-oxoacetamide (1.9g, 5.78 mmol) as described for compound I-44 to obtain the titlecompound I-46 (0.91 g, 51.7%) as a tan solid. ¹H NMR (CDCl₃): δ 8.16 (s,1H), 7.54-7.52 (m, 2H), 7.43-7.33 (m, 2H), 7.08 (t, 1H, J=6.0 Hz), 6.98(d, 1H, J=6.0 Hz), 6.90 (d, 1H, J=3.0 Hz), 6.57 (d, 1H, J=6.0 Hz),5.24-5.20 (m, 2H); ESI-MS (m/z, %): 305 (MH⁺, 100).

Synthesis of 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d₄)-1H-indol-4-ol(I-45)

A solution of2-(4-(benzyloxy)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d₄(0.88 g, 2.89 mmol)) in dry methanol (20 mL) was treated with Pd—C(0.25g) and hydrogenated under hydrogen atm. for additional 2 h. The reactionwas filtered through a pad of celite and washed with methanol (2×15 mL).Combined methanol layer was evaporated and crude was purified by flashcolumn chromatography (2M NH₃ in MeOH: CH₂Cl₂, 5:95) on silica gel toobtain the title compound to obtain the title compound I-45 (0.53 g,85.6%) as an off-white solid. ¹H NMR of TFA salt (DMSO-d₆): δ 10.81 (s,1H), 9.55 (s, 1H), 9.38 (s, 1H), 7.06 (d, 1H, J=1.5 Hz), 6.88-6.80 (m,2H), 6.38-6.36 (m, 1H); ESI-MS (m/z, %): 215 (MH+, 100).

Example 4: Synthesis of3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-yl dihydrogenphosphate (I-3)

A solution of 3-(2-(bis(methyl-d₃)amino)ethyl-1,1,2,2-d₄)-1H-indol-4-ol(1.1 g, 5.13 mmol) in dry THF (20 mL) was treated with n-butyl lithium(2.36 mL, 5.90 mmol) at −78° C. The reaction was treated withtetrabenzylpyrophosphate (3.59 g, 6.67 mmol) in dry THF (20 mL) afterstirring for 10 min. at same temperature. The reaction was brought to 0°C. over a period of 1 h and stirred for additional 1 h at sametemperature. The reaction was treated with aminopropyl silica gel (4.4g) and diluted with ethyl acetate (50 mL). The reaction was filteredthough a pad of celite and washed with ethyl acetate (2×50 mL). Combinedorganic layer was evaporated and dried under vacuum to obtain crudedibenzyl (3-(2-(bis(methyl-d₃)amino)ethyl-1,1,2,2-d4)-1H-indol-4-yl)phosphate as light brown semi-solid.

A solution of above crude dibenzyl(3-(2-(bis(methyl-d₃)amino)ethyl-1,1,2,2-d4)-1H-indol-4-yl) phosphate inmethanol (50 mL) was treated with Pd—C(0.5 g) and hydrogenated underhydrogen atm. for 2 h. water (15 mL) was added and hydrogenation wascarried for additional 14 h. The reaction was filtered through a pad ofcelite and washed with methanol (2×50 mL). Solvent was evaporated, driedunder high vacuum and crystallized from ethanol to obtain the titlecompound (1.2 g, 79%) as a light blue solid. ¹H NMR (D20): δ 7.26-7.16(m, 1H), 7.11-7.04 (m, 2H), 6.95 (d, 1H, J=6.0 Hz); ESI-MS (m/z, %): 295(MH+), 306 (100), 317 (M+Na).

B. Biological Testing

Example 5: FLIPR Assay: Human 5-HT2A

I. Assessment of the activated effect of compounds of Formula Itargeting on human 5-HT2A (h5-HT2A) receptor under agonist mode:

Compound Preparation and Assay Controls

I.a. Reagent and Materials:

Regents Vendor Cat# DMEM Gibco 10569010 FBS Hyclone SH30406Penicillin-Streptomycin Invitrogen 15140 Hygromycin B Invivogen Ant-hg-5G418 Invitrogen 11811031 Tetracycline hydrochloride Abeam ab141223 DPBSGibco 14190250 DMSO Millipore 1029312500 Probenecid Sigma P8761 FLIPRCalcium 6 Assay Kit Molecular Device R8191 HEPES Invitrogen 15630 Hank’sBuffered Saline Solution Invitrogen 14025 Serotonin HCl Selleck S4244

I.b. Instrumentation and Consumables:

Item Supplier Cat# Fluorometric Imaging Plate Reader Molecular DeviceTetra (FLIPR) Countess Automated Cell Counter Invitrogen Countess CellCounting Chamber Slides Invitrogen C10312 STERI-CYCLE CO₂ IncubatorThermo 371 1300 Series Class II Biological Safety Thermo 1389 CabinetTable-type Large Capacity Low Speed Cence L550 Centrifuge CentrifugeEppendorf 5702 Echo Labcyte 550 Echo Labcyte 655 Electro-thermalincubator Shanghai Yiheng DHP-9031 plate shaker IKA MS3 digital WaterPurification System ULUPURE UPH-III-20T Versatile and Universal pH andMettler Toledo S220 Conductivity Meters 384-Well plate Corning 356663384-Well LDV Clear microplate LABCYTE LP-0200 384-Well Polypropylenemicroplate LABCYTE PP-0200 384-well compound plate Corning 3657 T25 cellculture flask Corning 430639 50 mL Polypropylene Centrifuge Tube JETCFT011500 15 mL Polypropylene Centrifuge Tube JET CFT011150

I.c. Experimental Methods and Procedures:

1. Culture the cells in cell culture medium (DMEM containing 10% FBS, 1×penicillin-streptomycin 300 μg/ml G418 and 100 μg/ml hygromycin B) at37° C., 5% (v/v) CO2.

2. One day before the assays, detach the cell using TrypLE™ Express andcount cells using cell counter. Only cells with >85% viability are usedfor the assay.

3. Seed 20000 cells/well in 30 μl/well culture medium to a 384-well cellplate and incubate the cells overnight at 37° C., 5% (v/v) CO2.

4. On the assay day, prepare 2×dye solution following the manual of theFLIPR@ Calcium 6 Assay Kit: i. Dilute the dye with assay buffer(20 mMHEPES in 1×HBSS, PH7.4); ii. Add probenecid to the final concentrationof 5 mM; iii. Vortex vigorously for 1-2 minutes.

5. Remove medium from cell plate by flicking the cell plate on towelpapers.

6. Add 10 μl of assay buffer and 10 μl of 2×dye solution to each well ofthe cell plate.

7. Put the cell plate on plate shaker, agitate the plate at 600 rpm for2 minutes. Incubate the plate at 37° C. for 2 hours followed byadditional 15-minute incubation at 25° C.

8. Prepare 3×compound in assay buffer: a. Dilute reference compounds torequired concentration with DMSO. Add the compounds to a 384-wellcompound plate; b. Perform serial dilutions; c. Add 10 mM test compoundsto the compound plate, perform 3-fold serial dilutions. d. Transfer 60nl/well of compounds from source plate to a 384-well compound plate(Corning, 3657) by using an Echo; e. Add 20 μl/well assay buffer to thecompound plate; f. Mix the plate on plate shaker for 2 mins;

9. Put the cell plate, compound plate and tips into FLIPR, transfer 10μl of 3×compound to the cell plate per well with FLIPR.

II. Data Analysis

i. The normalized fluorescence reading (RFU) is calculated as shownfollow, while Fmax and Fmin stand for maximum and minimum of calciumsignal during defined time window: RFU=Fmax−Fmin

ii. Calculate the percentage activation by using following equation:

${\%{Activation}} = {\frac{\left( {{{RFU}{compound}} - {{RFU}{low}{control}}} \right)}{\begin{matrix}\left( {{{RFU}{top}{concertration}{of}{reference}{agonist}} -} \right. \\\left. {{RFU}{low}{control}} \right)\end{matrix}}*100\%}$

iii. Calculate EC₅₀ by fitting % activation against log of compoundconcentrations with Hill equation using XLfit.

The exemplary compounds of the application were found to be 5-HT2Aagonists. The results of representative compounds are presented as EC₅₀provided in Table 1. The letter “A” indicates an EC₅₀<1,000 nM; “B”indicates and EC₅₀>1,000 nM but <10,000 nM; and “C” indicates andEC₅₀>10,000 nM.

TABLE 1 Effect of exemplary compounds of Formula I targeting on human5-HT2A (h5-HT2A) receptor under agonist mode: h5-HT2A CompoundID#/Example EC50 [nM] Psilocin A (I-43) Example 1 A (1-44) Example 2 A(I-45) Example 3 A (I-3) Example 4 B

III. Results & Discussion

Exemplary compounds of Formula I were evaluated functionally using FLIPRassay for their effect on h5-HT2A receptor under agonist mode. EC₅₀ (nM)concentrations are illustrated in Table 1. This assay confirms thatcompounds of the application are effective agonists of the target human5-HT2A receptors.

Example 6: Human 5-HT2A: Radioligand Binding Assay

Materials and Instruments:

Materials Vendor Cat# Ketanserin Hydrochloride, PerkinElmer NET791250UC[Ethylene-3H]- Ketanserin MedChemExpress HY-10562 Bovine Serum Albumin(BSA) Sigma A1933 Calcium chloride (CaCl₂) Sigma C5670Tris(hydroxymethyl)aminomethane Alfa Aesar A18494 (Tris)Polyethylenimine, branched (PEI) Sigma 408727Instrumentation and Consumables:

Item Supplier Cat# Microbeta² Microplate Counter PerkinElmer 2450-0060UniFilter-96 GF/B PerkinElmer 6005177 TopSeal Biotss SF-800 MicroBetaFiltermate-96 PerkinElmer D961962 Seven Compact pH meter Mettler ToledoS220 Ultrapure Water Meter Sichuan Ulupure UPH-III-20T BenchtopCentrifuge Hunan Xiangyi L550 Microplate Shaker Allsheng MX100-4A384-Well Polypropylene Microplate Labcyte PP-0200 96 Round Well PlateCorning 3799 96 Round Deep Well Plate Axygen P-DW-11-C Echo LABCYTE 550Experiment Procedure:

i. Prepare the assay buffer following the table below; ReagentConcentration

Reagent Concentration Tris 50 mM CaCl₂  4 mM BSA 0.1% (w/v) Adjust pH to7.4 followed by 0.2 μM sterile filtration

ii. Preparation of 8 doses of reference and test compounds starting from10 mM stock solution as requested by 5-fold serial dilutions with 100%;

iii. Prepare (v/v) DMSO: a. Add 50 μl/well of 0.5% (v/v) PEI toUniFilter-96 GF/B plates. Seal the plates and incubate at 4° C. for 3hrs; b. After incubation, wash the plates 3 times with ice-cold washbuffer (50 mM Tris, pH7.4);

iv. Preparation of assay plates: a. Dilute cell membrane with assaybuffer and add 330 μl/well to 96 round deep well plates to reach aconcentration of 20 μg/well; b. Prepare 8 concentrations of reference orexemplary compounds of the application and add 110 μl/well to 96 rounddeep well plates; c. Dilute [3H]-ketanserin with assay buffer to 5 nM(5λ final concentration) and add 110 μl/well to 96 round deep wellplates.

v. Centrifuge the plate at 1000 rpm for 30 secs and then agitate at 600rpm, R.T. for 5 min.

vi. Seal the plates and incubate the plate at 27° C. for 90 min.

vii. Stop the incubation by vacuum filtration onto GF/B filter platesfollowed by 4 times washing with ice-cold wash buffer (50 mM Tris,pH7.4).

viii. Dry the plates at 37° C. for 45 min.

ix. Seal the filter plates and add 40 μl/well of scintillation cocktail.

x. Read the plate by using a Microbeta2 microplate counter.

Data Analysis:

For reference and exemplary test compounds of the application, theresults are expressed as % Inhibition, using the normalization equation:N=100−100×(U−C2)/(C1−C2), where U is the unknown value, C1 is theaverage of high controls, and C2 is the average of low controls. TheIC50 is determined by fitting percentage of inhibition as a function ofcompound concentrations with Hill equation using XLfit.

Results and Discussion:

The results of potential competition binding properties of therepresentative compounds targeting on human 5-hydroxytryptaminereceptors 2A (5-HT2A) are summarized in Table 2. The results ofrepresentative compounds are presented as IC50 provided in Table XX. Thesymbol “#” indicates an IC50<500 nM; “# #” indicates and IC50>500 nMbut<5,000 nM; and “# # #” indicates IC50>5,000 nM.

Table 2: Effect of exemplary compounds of Formula I using Radioligandbinding assay on human 5-HT2A receptor.

h5- HT2A IC50 Compound ID#/Example [nM] Psilocin # (1-43) Example 1 #(I-44) Example 2 # (I-45) Example 3 # (1-3) Example 4 ##

Exemplary compounds of Formula I were evaluated using radioligandbinding assay on human 5-HT2A receptor. EC₅₀ (nM) concentrations areillustrated in Table 2. This assay confirms that compounds of theapplication are effective ligands of the target human 5-HT2A receptor.

Example 7: Human, Rat and Mouse Liver Microsomes Stability

Objective

The objective of this study was to estimate in vitro metabolic stabilityof I-45 in pooled human and male mouse liver microsomes. Theconcentrations of exemplary compounds in reaction systems were evaluatedby LC-MS/MS for estimating the stability in pooled human and male mouseliver microsomes. The in vitro intrinsic clearances of test compoundswere determined as well.

Protocol

A master solution in the “Incubation Plate” containing phosphate buffer,ultra-pure H₂O, MgCl₂ solution and liver microsomes was made accordingto Table—. The mixture was pre-warmed at 37° C. water bath for 5minutes.

TABLE 3 Preparation of master solution Reagent Stock ConcentrationVolume Final Concentration Phosphate buffer 200 mM 200 μL  100 mMUltra-pure H₂O — 106 μL — MgCl₂ solution  50 mM  40 μL    5 mMMicrosomes  20 mg/mL  10 μL  0.5 mg/mL

40 μL of 10 mM NADPH solution was added to each well. The finalconcentration of NADPH was 1 mM. The negative control samples wereprepared by replacing NADPH with 40 μL of ultra-pure H₂O. Samples wereprepared in duplicate. Negative controls were prepared in singlet.

The reaction was started with the addition of 4 μL of 200 μM testcompounds or control compounds to each master solution to get the finalconcentration of 2 μM. This study was performed in duplicate.

Aliquots of 50 μL were taken from the reaction solution at 0, 15, 30, 45and 60 minutes. The reaction solutions were stopped by the addition of 4volumes of cold methanol with IS (100 nM alprazolam, 200 nM imipramine,200 nM labetalol and 2 μM ketoprofen). Samples were centrifuged at 3,220g for 40 minutes. Aliquot of 90 μL of the supernatant was mixed with 90μL of ultra-pure H2O and then was used for LC-MS/MS analysis.

LC/MS analysis was performed for all samples from this study using aShimadzu liquid chromatograph separation system equipped with degasserDGU-20A5R; solvent delivery unit LC-30AD; system controller SIL-30AC;column oven CTO-30A; CTC Analytics HTC PAL System. Mass spectrometricanalysis was performed using an Triple Quad™ 5500 instrument.

All calculations were carried out using Microsoft Excel. Peak arearatios of test compound to internal standard (listed in the below table)were determined from extracted ion chromatograms.

All calculations were carried out using Microsoft Excel. Peak areas weredetermined from extracted ion chromatograms. The slope value, k, wasdetermined by linear regression of the natural logarithm of theremaining percentage of the parent drug vs. incubation time curve.

The in vitro half-life (in vitro t_(1/2)) was determined from the slopevalue:in vitro t _(1/2)=−(0.693/k)

Conversion of the in vitro t_(1/2) (min) into the in vitro intrinsicclearance (in vitro CL_(int), in μL/min/mg proteins) was done using thefollowing equation (mean of duplicate determinations):

${{in}{vitro}{CL}_{int}} = {\left( \frac{0.693}{\left( t_{1/2} \right)} \right)*\left( \frac{{volume}{of}{incubation}\left( {\mu L} \right)}{{amount}{of}{{proteins}{}({mg})}} \right)}$For the exemplary compound of the application or control compound thatshowed an initial fast disappearance followed by a slow disappearance,only the time points that were within the initial rate were included inthe calculation. Results & Discussion

Human, rat and mouse liver microsomes contain a wide variety of drugmetabolizing enzymes and are commonly used to support in vitro ADME(absorption, distribution, metabolism and excretion) studies. Thesemicrosomes are used to examine the potential first-pass metabolismby-products of orally administered drugs. Exemplary compounds of theapplication were evaluated for their stability in human, rat and mouseliver microsomes. A majority of the compounds of the application inthree species, human, rat and mouse liver microsomes were recoveredwithin a 60 minute time period indicating that the compounds were notrapidly cleared (see Table 4 for representative compounds of Formula I).

TABLE 4 Metabolic stability of representative example of Formula I andcontrol compound verapamil in human, rat and mouse with NADPH RemainingPercentage (%) t_(1/2) CL_(int) Compound after 60 min (min) (μL/min/mgprotein) ID# Human Rat Mouse Human Rat Mouse Human Rat Mouse Verapamil3.81 1.73 1.73 14.21 9.70 10.25 97.5 142.92 135.18 Psilocin 70.16 62.6896.89 117.32 89.01 141.71 11.81 15.57 9.78 (1-45) 73.65 3.34 64.91135.96 12.23 96.22 10.19 113.28 14.40 Example 3

Example 8: In Viva Assessment of the Pharmacokinetics in Mice and Rats

1. Formulation Preparation and Storage

Group ID Formulation Storage 1, 3, 5, 7 & 9 A 0.2 mg/mL formulation ofthe −80° C. appropriate TA will be freshly prepared in saline on the dayof dosing. 2, 4, 6, 8 & 10 A 1 mg/mL formulation of the appropriate TAwill be freshly prepared in saline on the day of dosing.

2. Sample Collection

Volume/ Group ID Blood collection time (h) time-point 1, 3, 5, 7 & 90.0833, 0.25, 0.5, 1, 2, 4, 6 & 8 ~0.03 mL (tail snip in mouse) 24 ~0.4mL blood via cardiac puncture 2, 4, 6, 8 & 10 0.25, 0.5, 1, 2, 4, 6, & 8~0.03 mL (tail snip in mouse) 24 ~0.4 mL blood via cardiac puncture

3. Study Details

Animals:

Male C57BL/6 mice (25-30 g) and male Sprague-Dawley rats (250-325 g)from Charles River Labs were acclimatized for a minimum of 5 days priorto dosing. Body weights were recorded on the day of dosing.

Food Restriction:

Animals dosed p.o. were deprived of food overnight and fed ˜2 hfollowing dosing.

Clinical Observations:

Animals were observed at the time of dosing and each sample collection.Any abnormalities will be documented.

Dosing:

Formulations were administered intravenously (i.v.) via the tail vein ororally (p.o.) by gavage with disposable feeding needles.

Sample Collection:

Serial blood samples were collected via tail snip. Terminal bloodsamples were collected under isoflurane anesthesia by cardiac puncture.

Sample Processing/Storage:

All blood samples were transferred into K₂EDTA tubes on wet ice andcentrifuged within 5 min (3200×g for 5 min at 4° C.) to obtain plasma.Plasma was stored at −80° C. until analysis.

Sample Retention:

Plasma samples were analyzed and any remaining samples were storedfrozen at −80° C. until the study is completed.

4. Bioanalytical Method Development and Sample Analysis

Matrix:

Mouse or Rat Plasma, as Applicable.

Instrumentation:

AB Sciex QTRAP 4000 or 6500 MS/MS system equipped with an LC system witha binary pump, a solvent degasser, a thermostatted column compartmentand a multiplate autosampler.

5. Method Development:

i. selection of the ion transition for the test compounds (i.e.identification of the parent and product ions).

ii. optimization of mass spectrometric operating parameters.

iii. establishment of the chromatographic conditions.

iv. selection of an appropriate internal standard(s) (IS).

v. sample clean-up method using protein precipitation.

6. Method Qualification:

i. the determination of the quantification dynamic range using non-zerocalibration standards (STDs) in singlet. The STDs consisted of a blankmatrix sample (without IS), a zero sample (with IS), and at least 6non-zero STDs covering the expected range and including the lower levelof quantitation (LLOQ).

ii. 3 injections of a system suitability sample (neat solutioncontaining the analyte and IS) bracketing the batch.

7. Method Acceptance Criteria:

i. at least 75% of non-zero STDs were included in the calibration curvewith all back-calculated concentrations within ±20% deviation fromnominal concentrations (±25% for the lower level of quantification,LLOQ).

ii. the correlation coefficient (r) of the calibration curve was greaterthan or equal to 0.99.

iii. the area ratio variation between the pre- and post-run injectionsof the system suitability samples is within ±25%.

8. Sample Analysis Batch:

i. 3 injections of a system suitability sample bracketing the batch.

ii. the STDs in ascending order.

iii. the study samples and the dosing solutions diluted as 3 independentdilutions into blank matrix (plasma).

iv. for more than 40 study samples in a batch, two sets of STDsbracketing the samples were utilized.

v. samples which were 25% greater than the highest calibration standard,were diluted and re-assayed along with a corresponding dilution qualitycontrol standard. Dilution standards were acceptable if they were within25% accuracy of the target concentration.

9. PK Analysis

i. Analysis software: Phoenix® WinNonlin® 8.2 (Pharsight, Certara,Mountainview, Calif.)

ii. Analysis methods: non-compartmental analysis, linear up/log downtrapezoidal rule

iii. PK parameters: C₀, t_(1/2), AUC_(0-tlast). AUC_(0-∞), CL, V_(ss),MRT, t_(max(po)), C_(max(po)), F, as appropriate

10. Results and discussion

TABLE 5 Pharmacokinetic parameters for exemplary compound 1-45 followingi.v administration to male C57BL/6 mice at 1 mg/kg Male C57BL/6 mice(I.V. Dosing) Parameter I-45 (Example 3) Dose (mg/kg) 1 C₀ (ng/mL)  566± 85.0 t_(max) (h) n/a C_(max) (ng/mL) n/a C_(max)/Dose (kg*ng/mL/mg)n/a Apparent t_(1/2) (h) 5.32 ± 2.99 AUC_(0-tlast)(h * ng/mL)  178 ±32.2 AUC_(0-inf) (h * ng/mL)  181 ± 30.8 AUC_(0-inf)/Dose  181 ± 30.8(h * kg * ng/mL/mg) CL (mL/h/kg) 5640 ± 895  MRT_(0-inf)(h)  1.49 ±0.536 V_(ss)(mL/kg) 8340 ± 3150 f_(m) n/a

TABLE 6 Pharmacokinetic parameters for exemplary compound 1-45 followingp.o. administration to male C57BL/6 mice at 10 mg/kg. Male C57BL/6 mice(P.O. Dosing) Parameter I-45 (Example 3) Dose (mg/kg) 10 t_(max) (h)0.250 ± 0.00  C_(max) (ng/mL) 704 ± 128 C_(max)/Dose (kg * ng/mL/mg)70.4 ± 12.8 Apparent t_(1/2) (h)  4.52 ± 0.481 AUC_(0-tlast) (h * ng/mL)792 ± 120 AUC_(0-inf) (h * ng/mL) 795 ± 121 AUC_(0-inf)/Dose 79.5 ± 12.1(h * kg * ng/mL/mg) MRT_(0-inf) (h)  2.00 ± 0.227 F (%) 44.0 ± 6.70 C₀concentration extrapolated to time zero following an i.v. dose t_(max)time at which maximum concentration is observed C_(max) maximum observedconcentration Apparent t_(1/2) apparent terminal half-life AUC_(0-tlast)area under the concentration vs time curve from time 0 to the time ofthe last measurable concentration AUC_(0-inf) area under theconcentration vs time curve from time 0 to infinity CL systemicclearance MRT_(0-inf) mean residence time from time zero to infinityV_(ss) steady-state volume of distribution F bioavailability =(Dose^(iv) * AUC^(po))/(Dose^(po) * AUC^(iv)) * 100

TABLE 7 Pharmacokinetic parameters for exemplary compound 1-45 followingi.v administration to male Sprague-Dawley rats at 0.3 mg/kg Male SpragueDawley rat (i.v. Dosing) Parameter 1-45 (Example 3) Dose (mg/kg) 0.3 C₀(ng/mL) 76.5 ± 7.49 t_(max) (h) n/a C_(max) (ng/mL) n/a C_(max)/Dose(kg * ng/mL/mg) n/a Apparent t_(1/2) (h) 34.6 ± 3.17 AUC_(0-tlast) (h *ng/mL) 35.2 ± 3.45 AUC_(0-inf) (h * ng/mL)  117 ± 11.5 AUC_(0-inf)/Dose 181 ± 30.8 (h * kg * ng/mL/mg) CL (mL/h/kg) 8590 ± 874  MRT_(0-inf) (h) 1.49 ± 0.536 V_(ss) (mL_/kg) 0.945 ± 0.142 f_(m) n/a

TABLE 8 Pharmacokinetic parameters for exemplary compound 1-45 followings.c. administration to male Sprague-Dawley rats at 0.3 mg/kg Parameter1-45 (Example 3) Dose (mg/kg) 0.3 t_(max) (h) 0.278 ± 0.210 C_(max)(ng/mL) 30.2 ± 12.2 C_(max)/Dose (kg * ng/mL/mg)  101 ± 40.7 Apparentt_(1/2) (h)^(a) 0.647 ± 0.212 AUC_(0-tlast) (h * ng/mL) 32.0 ± 9.20AUC_(0-inf) (h * ng/mL) 35.9 ± 8.71 AUC_(0-inf)/Dose  120 ± 29.0 (h *kg * ng/mL/mg) MRT_(0-inf) (h) 0.991 ± 0.228 F (%)  125 ± 30.4

TABLE 9 Pharmacokinetic parameters for exemplary compound I-45 followingp.o administration to male Sprague-Dawley rats at 3.0 mg/kg Male SpragueDawley rat (p.o. Dosing) Parameter 1-45 (Example 3) Dose (mg/kg) 10t_(max) (h) 0.333 ± 0.144 C_(max) (ng/mL)  238 ± 73.3 C_(max)/Dose (kg *ng/mL/mg) 79.2 ± 24.4 Apparent t_(1/2) (h)  2.61 ± 0.795 AUC_(0-tlast)(h * ng/mL)  534 ± 38.7 AUC_(0-inf) (h * ng/mL)  543 ± 43.7AUC_(0-inf)/Dose  181 ± 14.6 (h * kg * ng/mL/mg) MRT_(0-inf) (h)  2.77 ±0.486 F (%)  155 ± 12.4 C₀ concentration extrapolated to time zerofollowing an i.v. dose t_(max) time at which maximum concentration isobserved C_(max) maximum observed concentration Apparent t_(1/2)apparent terminal half-life AUC_(0-tlast) area under the concentrationvs time curve from time 0 to the time of the last measurableconcentration AUC_(0-inf) area under the concentration vs time curvefrom time 0 to infinity CL systemic clearance MRT_(0-inf) mean residencetime from time zero to infinity V_(ss) steady-state volume ofdistribution F bioavailability = (Dose^(iv) * AUC^(po))/(Dose^(po) *AUC^(iv)) * 100

Example 9: Psychedelic-Like Effects of Exemplary Compounds of Formula I

The effect of different doses of exemplary compounds of Formula I wereevaluated on head-twitch response (HTR) as a behavior-based model ofpsychedelic activity.

1. Protocols

Mouse Head Twitch

Male, C57BL/6J mice (body weight range 20-30 g) were dosed with theappropriate dose of test article, and following a 1-minute pre-treatmenttime, placed in individual observation chambers. Animals were visuallyassessed for the incidence head twitches continuously over a 1 hrperiod. Head twitches were defined as a rapid jerk of the head which wasnot elicited by an external tactile stimulus (Corne and Pickering,Psychopharmacologia, 1967, 11(1): 65-78). Each head twitch wasindividually counted by a trained observer, and the data expressed asthe mean+SEM of 6-10 mice per group. Mice were used in a singleexperiment only.

Rat Behavioural Test

Male, Sprague-Dawley rats (body weight range 250-400 g) are dosed withthe appropriate dose of test article and following a 1-minutepre-treatment time, placed in locomotor activity boxes (dimensions 17″W×17″ L×12″ H) and continuously monitored for a 1 hr period with datacollected into 10 minute time bins. Animals are visually assessed forovert behavioural signs, including behaviours characteristic of 5-HT2Areceptor activation (wet dog shakes, back muscle contractions), 5-HT2Areceptor activation (yawning, penile grooming) and 5-HT1A behaviours(forepaw treading, hindlimb abduction) (Halberzettl et al, Behav BrainRes. 256: 328-345, 2013). Additional behavioural and somatic signscharacteristic of 5-HT syndrome (e.g. tremor, salivation, flat bodyposture, core body temperature change) are also measured.Simultaneously, the spontaneous activity of the rats is measured usingan automated tracking system (Med Associates, VT, USA). Activity datacollected includes total distance traveled, rearing counts andambulatory episodes. All data are expressed as the mean+SEM of 6-10 ratsper group.

Drug Discrimination in the Rat

Male Sprague-Dawley rats are initially food restricted by presentationof 18-20 g food at day end (single housing). After 7 daysacclimatisation to the food restriction procedure, they are traineddaily to lever press for food (45 mg Bioserve pellet) in standard2-lever operant conditioning chambers controlled by Med-PC software overa period of 1 week (Med. Associates Ins., St. Albans, Vt.). The rats aretrained to lever press for food to an FR10 value (i.e 10 lever pressesfor a single food reward). Once stable food responding is acquired toboth response levers, discrimination training began. Over a period of20-50 training sessions, the rats are trained to associate one lever toa psilocybin training dose of 1 mg/kg SC, and the second lever to aneutral stimulus (saline, SC) (Winter et al, Pharmacol Biochem Behav.87(4): 472-480, 2007). Training sessions last 30-min or until thedelivery of 50 pellets and continue until the animals attain appropriatestimulus control (defined as six consecutive sessions where animals makeno more than 16 lever presses before the delivery of the first reward,and at least 95% total responses on the appropriate lever). The ratscontinue to receive daily food ration in their home cage at day end.

Once trained, tests of substitution are conducted. On test days, bothlevers are designated active, i.e., every 10th response on either leverresults in delivery of a food pellet. Test sessions continue until 50pellets have been obtained or 30 min has elapsed. During these sessionsresponse rate is also measured.

Results and Discussion

Exemplary compound I-45: Dose response (0.3-10 mg/kg SC) vs 5-HT2A signsof mouse head twitch measured over 1 h (Table 9; FIG. 1 ). Also,locomotor activity and other 5-HT receptor signs were measured. Miceshowed a dose dependent increase in head twitch frequency compared tovehicle control, which is consistent with 5HT2A activation andassociated with the hallucinogenic response in humans.

TABLE 9 Dose response versus mouse head twitch measured over 1 h BodyHead Twitch Animal Treatment Weight 10 20 30 40 50 60 ID (mg/kg) (g)mins mins mins mins mins mins Total O1 Vehicle 25.1 0 1 0 0 0 0 1 O229.5 0 0 0 0 0 0 0 O3 21.5 0 0 0 0 0 0 0 O4 19.3 1 0 0 0 0 0 1 O5 20.3 00 0 0 0 0 0 O6 19.7 0 0 0 0 0 0 0 AVG 22.6 0.2 0.2 0.0 0.0 0.0 0.0 0.3SEM 1.6 0.2 0.2 0.0 0.0 0.0 0.0 0.2 C1 I-45 23.2 0 0 0 0 0 0 0 C2 (0.03mg/kg) 24.4 1 0 0 0 0 0 1 C3 25.0 3 0 0 0 1 0 4 C4 24.4 2 0 0 0 0 0 2 C523.3 2 0 0 0 0 0 2 C6 25.1 0 1 0 0 0 0 1 AVG 24.2 1.3 0.2 0.0 0.0 0.20.0 1.7 SEM 0.3 0.5 0.2 0.0 0.0 0.2 0.0 0.6 P1 I-45 26.3 3 1 0 1 0 0 5P2 (0.1 mg/kg) 28.6 6 0 1 0 2 0 9 P3 25.5 0 2 1 0 0 0 3 P4 28.7 1 0 0 10 0 2 P5 27.7 0 0 0 0 1 0 1 P6 28.5 2 1 1 0 0 0 4 P7 25.1 1 1 0 0 0 0 2P8 21.8 0 2 0 0 0 0 2 P9 25.2 1 1 1 0 0 0 3 P10 24.3 2 0 0 0 1 0 3 AVG26.2 1.6 0.8 0.4 0.2 0.4 0.0 3.4 SEM 0.7 0.6 0.2 0.2 0.1 0.2 0.0 0.7 Q1I-45 26.0 3 0 1 0 0 0 4 Q2 (0.3 mg/kg) 27.6 1 1 0 0 0 0 2 Q3 26.1 0 0 10 0 0 1 Q4 27.7 1 1 0 0 0 0 2 Q5 26.9 2 1 0 1 0 0 4 Q6 28.9 2 1 0 0 0 03 Q7 22.5 1 1 3 0 1 0 6 Q8 23.6 2 1 1 0 0 0 4 Q9 24.7 0 0 0 0 0 0 0 Q1025.1 1 0 0 2 1 0 4 AVG 25.9 1.3 0.6 0.6 0.3 0.2 0.0 3.0 SEM 0.6 0.3 0.20.3 0.2 0.1 0.0 0.6 R1 I-45 27.1 0 0 1 0 0 0 1 R2 (1 mg/kg) 27.2 4 2 0 00 0 6 R3 29.9 1 1 0 0 0 0 2 R4 26.1 3 0 0 0 0 0 3 R5 30.6 3 7 3 2 0 0 15R6 27.1 3 8 1 2 0 0 14 AVG 28.0 2.3 3.0 0.8 0.7 0.0 0.0 6.8 SEM 0.7 0.61.5 0.5 0.4 0.0 0.0 2.5 S1 I-45 26.1 1 2 2 2 1 0 8 S2 (3 mg/kg) 25.3 3 11 0 0 0 5 S3 27.0 1 2 0 0 0 0 3 S4 25.5 2 0 1 0 1 0 4 S5 26.8 6 3 2 3 00 14 S6 27.2 0 5 1 0 0 1 7 AVG 26.3 2.2 2.2 1.2 0.8 0.3 0.2 6.8 SEM 0.30.9 0.7 0.3 0.5 0.2 0.2 1.6 T1 I-45 28.5 3 1 0 0 0 0 4 T2 (10 mg/kg)30.0 1 0 0 1 0 0 2 T3 28.3 1 0 0 1 0 3 5 T4 29.3 0 0 0 0 0 0 0 T5 26.0 01 0 0 0 0 1 T6 30.0 0 0 0 0 0 0 0 AVG 28.7 0.8 0.3 0.0 0.3 0.0 0.5 2.0SEM 0.6 0.5 0.2 0.0 0.2 0.0 0.5 0.9

While the present application has been described with reference toexamples, it is to be understood that the scope of the claims should notbe limited by the embodiments set forth in the examples, but should begiven the broadest interpretation consistent with the description as awhole.

All patents, patent applications and publications cited herein arehereby incorporated by reference in their entirety. The disclosures ofthese publications in their entireties are hereby incorporated byreference into this application in order to more fully describe thestate of the date of the application described and claimed herein.

The invention claimed is:
 1. A compound of Formula I-2 or apharmaceutically acceptable salt, solvate or prodrug thereof:


2. A compound of Formula I-2, or a pharmaceutically acceptable salt orsolvate thereof:


3. A composition comprising the compound of claim 1, or apharmaceutically acceptable salt, solvate or prodrug thereof.
 4. Acomposition comprising the compound of claim 2, or a pharmaceuticallyacceptable salt or solvate thereof.
 5. A pharmaceutical compositioncomprising the compound of claim 1, or a pharmaceutically acceptablesalt or solvate.
 6. The composition of claim 5, wherein the compositionfurther comprises a pharmaceutically acceptable carrier.
 7. Thecomposition of claim 6, wherein the composition is suitable for oraladministration.
 8. The composition of claim 6, wherein the compositionis suitable for intravenous (IV) administration.
 9. The composition ofclaim 7, wherein the composition is a tablet, buccal tablet, troch,capsule, caplet, pellet, granule, lozenge, chewing gum, powder, syrup,elixir, wafer, aqueous solution or suspension.
 10. The composition ofclaim 5, wherein the composition comprises 0.1 mg to 1000 mg of thecompound of Formula I-2, or a pharmaceutically acceptable salt orsolvate thereof.
 11. The composition of claim 5, wherein the compositioncomprises 500 mg of the compound of Formula I-2, or a pharmaceuticallyacceptable salt or solvate thereof.
 12. The composition of claim 5,wherein the composition comprises 10 mg to 250 mg of the compound ofFormula I-2, or a pharmaceutically acceptable salt or solvate thereof.13. The composition of claim 5, wherein the composition comprises 0.5 mgto 250 mg of the compound of Formula I-2, or a pharmaceuticallyacceptable salt or solvate thereof.
 14. The composition of claim 5,wherein the composition comprises 0.5 mg to 50 mg of the compound ofFormula I-2, or a pharmaceutically acceptable salt or solvate thereof.15. The composition of claim 5, wherein the composition comprises 10 mgto 50 mg of the compound of Formula I-2, or a pharmaceuticallyacceptable salt or solvate thereof.
 16. The composition of claim 5,comprising the compound of Formula I-2, or a pharmaceutically acceptablesalt thereof.
 17. A method for activating a serotonin receptor in asubject comprising administering the compound of claim 1, or apharmaceutically acceptable salt, solvate or prodrug thereof, to thesubject.
 18. A method of treating a subject having a condition that istreated by activation of a serotonin receptor, comprising administeringthe compound of claim 1, or a pharmaceutically acceptable salt solvateor prodrug thereof.
 19. The method of claim 18, wherein the condition isa neurological or psychiatric disorder.
 20. The method of claim 18,wherein the condition is psychosis or psychotic symptoms.
 21. The methodof claim 18, wherein the condition is a mental illness disorder.
 22. Themethod of claim 21, wherein the mental illness disorder is selected fromgeneralized anxiety disorders, phobias, depression, mood disorders,psychotic disorders, eating disorders, impulse control disorders,addiction disorders, personality disorders, dissociative disorders,factitious disorders, sexual disorders, gender disorders, somaticsymptom disorders, attentional disorders, tic disorders, sleep-relateddisorders, and a combination thereof.
 23. The method of claim 21,wherein the mental illness disorder is selected from panic disorder,social anxiety disorder, hopelessness, loss of pleasure, fatigue,suicidal thoughts, bipolar disorder, cancer-related depression, anxiety,cyclothymic disorder, hallucinations, delusions, schizophrenia, anorexianervosa, bulimia nervosa, binge eating disorder, pyromania, kleptomania,compulsive gambling, alcohol addiction; drug addiction, antisocialpersonality disorder, obsessive-compulsive personality disorder,paranoid personality disorder; obsessive-compulsive disorder (OCD),post-traumatic stress disorder (PTSD), stress response syndromes, sexualdysfunction, gender identity disorder, paraphilia, attentional deficitdisorder, attentional deficit hyperactivity disorder, Tourette'ssyndrome, and a combination thereof.
 24. The method of claim 21, whereinthe mental illness disorder is selected from hallucinations, delusions,and a combination thereof.
 25. The method of claim 24, wherein thehallucinations are selected from visual hallucinations, auditoryhallucinations, olfactory hallucinations, gustatory hallucinations,tactile hallucinations, proprioceptive hallucinations, equilibrioceptivehallucinations, nociceptive hallucinations, thermoceptivehallucinations, chronoceptive hallucinations and a combination thereof.26. The method of claim 21, wherein the mental illness disordercomprises cognitive impairment, ischemia, neurodegeneration, refractorysubstance use disorders, sleep disorders, pain, obesity, eatingdisorders, seizure disorders, neuronal cell death, excitotoxic calldeath, or a combination thereof.
 27. The method of claim 18, wherein thecondition is a CNS disorder that is a form of dementia.
 28. The methodof claim 18, comprising administering the compound of Formula I-2, or apharmaceutically acceptable salt or solvate thereof.
 29. The method ofclaim 18, wherein the subject is a feline or canine and the condition isanxiety, fear, stress, sleep disturbances, cognitive dysfunction,aggression, or a combination thereof.